TOMM6-INTERACTING EXTRACTS AND COMPOUNDS FOR USE IN THE TREATMENT AND PROPHYLAXIS OF NERVOUS SYSTEM DISEASES, ATHEROSCLEROSIS, HEPATITIS B INFECTION AND HUMAN PAPILLOMA VIRUS (HPV) INFECTION
20210186947 · 2021-06-24
Inventors
Cpc classification
A61K36/70
HUMAN NECESSITIES
A61K36/72
HUMAN NECESSITIES
A61K31/192
HUMAN NECESSITIES
A61K31/122
HUMAN NECESSITIES
A61P9/10
HUMAN NECESSITIES
A61K31/4439
HUMAN NECESSITIES
A61K31/4418
HUMAN NECESSITIES
A61P25/28
HUMAN NECESSITIES
A61K36/72
HUMAN NECESSITIES
A61K2300/00
HUMAN NECESSITIES
A61K2300/00
HUMAN NECESSITIES
A61K36/48
HUMAN NECESSITIES
A61K31/454
HUMAN NECESSITIES
A61K36/70
HUMAN NECESSITIES
International classification
A61K31/454
HUMAN NECESSITIES
A61K31/122
HUMAN NECESSITIES
A61K31/192
HUMAN NECESSITIES
A61K31/4418
HUMAN NECESSITIES
A61K31/4439
HUMAN NECESSITIES
A61P25/28
HUMAN NECESSITIES
Abstract
The present invention is directed to a TOMM6 (Translocase of Outer Membrane 6 kDa subunit homologue; Mitochondrial import receptor subunit TOM6 homolog)-interacting plant or fungal extract comprising an anthraquinone or anthraquinone derivative, a TOMM6-interacting anthraquinone or anthraquinone derivative, and TOMM6-interacting compounds for use in the treatment or prophylaxis of a nervous system disease, atherosclerosis, Hepatitis B infection and/or human papilloma virus (HPV) infection. Furthermore, the present invention relates to a corresponding method of therapeutic or prophylactic treatment of a nervous system disease or disorder, atherosclerosis, Hepatitis B infection and/or human papilloma virus (HPV) infection, as well as to a method for the identification of a TOMM6-interacting compound or composition. Also, the present invention provides a non-human transgenic animal expressing a transgenic, preferably human TOMM6 or a TOMM6 homolog.
Claims
1.-19. (canceled)
20. A method for the therapeutic or prophylactic treatment of a disease comprising the steps of: administering to a patient in need thereof a therapeutically or prophylactically effective amount of TOMM6 (Translocase of Outer Membrane 6 kDa subunit homolog)-interacting compound or composition selected from the group consisting of: (i) a plant or fungal extract comprising an anthraquinone or anthraquinone derivative selected from the group of compounds of formula (IIIa) and (IIId): ##STR00024## wherein for Formula (IIIa): R.sup.1, R.sup.3, R.sup.6, R.sup.7, and R.sup.8 are each independently selected from the group consisting of: a) H, F, Cl, Br, —OH, —CN, —OSO.sub.3H and —SO.sub.3H; b) —O(C.sub.1-10)alkyl, —O(C.sub.3-10)cycloalkyl, —O(C═O)(C.sub.1-10)alkyl, or —O(C═O)(C.sub.3-10)cycloalkyl; c) —COOH, —COO(C.sub.1-10)alkyl, —COO(C.sub.3-6)cycloalkyl, —COONH.sub.2, —COON((C.sub.1-10)alkyl).sub.2, —COONH(C.sub.1-10)alkyl; d) linear or branched, substituted or non-substituted (C.sub.2-10)alkyl ether, (C.sub.3-10)alkenyl ether, (C.sub.3-10)alkynyl ether or (C.sub.4-10)carbocyclic ether, wherein the ether is bonded to formula (III), (IV) or (V) via its carbon atom; e) linear or branched, substituted or non-substituted (C.sub.1-10)alkyl, (C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl; f) substituted or non-substituted carbocycle selected from the group consisting of (C.sub.3-10)carbocycle; g) substituted or non-substituted (C.sub.3-6)heterocycle or (C.sub.7-10)carbo- or hetero-bicycle having 1 to 3 heteroatoms each independently selected from N, O and S; and h) a mono- or polysaccharide, wherein the mono- or polysaccharide ring carbon is directly attached or attached via an oxygen atom; wherein for Formula (IIId): R.sup.1 to R.sup.8 are each independently selected from the group consisting of: a) H, F, Cl, Br, —CN, —OH, —OSO.sub.3H and —SO.sub.3H; b) —O(C.sub.1-6)alkyl, —O(C.sub.3-6)cycloalkyl, —O(C═O)(C.sub.3-6)cycloalkyl; c) —COOH, —COO(C.sub.1-10)alkyl, —COO(C.sub.3-6)cycloalkyl, —COONH.sub.2, —COON((C.sub.1-10)alkyl).sub.2, or —COONH(C.sub.1-10)alkyl; d) linear or branched, substituted or non-substituted (C.sub.2-10)alkyl ether, (C.sub.3-10)alkenyl ether, (C.sub.3-10)alkynyl ether or (C.sub.4-10)carbocyclic ether, wherein the ether is bonded to formula (IIId) via its carbon atom; e) linear or branched, substituted or non-substituted (C.sub.1-10)alkyl, (C.sub.2-10)alkenyl, or (C.sub.2-10)alkynyl, substituted or non-substituted —CHO; f) substituted or non-substituted carbocycle selected from the group consisting of (C.sub.3-10)carbocycle; and g) substituted or non-substituted (C.sub.3-6)heterocycle or (C.sub.7-10)carbo- or hetero-bicycle having 1 to 3 heteroatoms each independently selected from N, O and S; and/or R.sup.2 and R.sup.3 together form a ring selected from the group consisting of: a) substituted or non-substituted (C.sub.3-10)carbocycle; and b) substituted or non-substituted (C.sub.3-6)heterocycle or (C.sub.7-10)carbo- or hetero-bicycle having 1 to 3 heteroatoms each independently selected from N, O and S, and pharmaceutically acceptable salts and solvates thereof; (ii) an anthraquinone or anthraquinone derivative selected from the group of compounds of Formula (IIIa) and (IIId) as defined in (i); and (iii) a compound according to Formula (II): ##STR00025## wherein for Formula (II): R.sup.2 to R.sup.6 are each independently selected from the group consisting of (i) H, Cl, Br, F, —CN, or —OH, (ii) —O(C.sub.1-10)alkyl or —O(C.sub.3-10)cycloalkyl, (iii) —O(C═O)(C.sub.1-10)alkyl, or —O(C═O)(C.sub.3-10)cycloalkyl, (iv) —COOH, —COO(C.sub.1-10)alkyl, —COO(C.sub.3-6)cycloalkyl, —COONH.sub.2, —COON((C.sub.1-10)alkyl).sub.2, or —COONH(C.sub.1-10)alkyl, R.sup.7 is selected from the group consisting of: (i) NH.sub.2, NH(C.sub.1-10)alkyl, —OH, —O(C.sub.1-10)alkyl, or —CN; (ii) —COOH, —COO(C.sub.1-10)alkyl, —COO(C.sub.3-6)cycloalkyl, —COONH.sub.2, —COON((C.sub.1-10)alkyl).sub.2, or —COONH(C.sub.1-10)alkyl; (iii) substituted or non-substituted carbocycle selected from the group consisting of (C.sub.3-10)carbocycle; and (iv) substituted or non-substituted (C.sub.3-6)heterocycle or (C.sub.7-10)carbo- or hetero-bicycle having 1 to 3 heteroatoms each independently selected from N, O and S; R.sup.8 is selected from the group consisting of —C(═O)NH.sub.2, —CN (instead of R.sup.8—CO), —C(═O)NH(C.sub.1-10)alkyl, —C(═O)OH, or —C(═O)O(C.sub.1-10)alkyl; R.sup.9 is selected from the group consisting of: (i) —H, -Me, -Et, halogen; (ii) —COOH, —COO(C.sub.1-10)alkyl, —COO(C.sub.3-6)cycloalkyl, —COONH.sub.2, —COON((C.sub.1-10)alkyl).sub.2, or —COONH(C.sub.1-10)alkyl; (iii) —OH, —O(C.sub.1-10)alkyl, or —O(C.sub.3-10)cycloalkyl; (iv) substituted or non-substituted (C.sub.3-10)carbocycle; and c is an integer between 0 and 4; and pharmaceutically acceptable salts and solvates thereof, wherein the disease is selected from the group consisting of: (a) a nervous system disease or disorder; (b) atherosclerosis; (c) Hepatitis B infection; and (d) human papilloma virus (HPV) infection.
21. The method according to claim 20, wherein the disease or disorder is a human nervous system disease or disorder, a central nervous system (CNS) or a peripheral nervous system (PNS) disease or disorder.
22. The method according to claim 20, wherein for Formula (II), R.sup.2 to R.sup.6 are each independently selected from the group consisting of: (i) H, Cl, Br, F, —CN, or —OH; (ii) —OMe and —OEt; (iii) —O(C═O)Me; and (iv) —COOH, —COOMe or COOEt; R.sup.7 is selected from the group consisting of: (i) —NH.sub.2 or —OH; (ii) —COOH, —COOMe or COOEt; (iii) (C.sub.3)carbocycle, (C.sub.5-6)carbocycle and aromatic (C.sub.6)carbocycle; and (iv) substituted or non-substituted (C.sub.3-6)heterocycle or (C.sub.7-10)carbo- or hetero-bicycle having 1 to 3 heteroatoms each independently selected from N, O and S; R.sup.8 is selected from the group consisting of —C(═O)NH.sub.2 and —CN; and R.sup.9 is selected from the group consisting of: (i) —F, or —CN; (ii) —COOH, —COOMe or COOEt; (iii) —OMe and —0Et, or —O(C.sub.3-10)cycloalkyl; and (iv) substituted or non-substituted (C.sub.3)carbocycle and (C.sub.5-6)carbocycle.
23. The method according to claim 22, wherein R.sup.4 is Cl and R.sup.2, R.sup.3, R.sup.5 and R.sup.6 are H; or R.sup.2 and R.sup.4 are Cl and R.sup.3, R.sup.5 and R.sup.6 are H; R.sup.7 is selected from the group consisting of (i) a non-substituted phenyl or a phenyl that is substituted by a substituent selected from the group consisting of Cl, F, Br, substituted or non-substituted methyl, preferably —(CF.sub.3), ethyl, propyl and cyclopropyl; and (ii) substituted or non-substituted heterobicycle having 1 nitrogen atom, isoindoline-1,3-dione, or ##STR00026## and R.sup.9 is selected from the group consisting of aromatic (C.sub.6)carbocycle, non-substituted phenyl or phenyl substituted by a substituent selected from the group consisting of Cl, F, Br, substituted or non-substituted methyl, —(CF.sub.3), ethyl, propyl and cyclopropyl.
24. The method according to claim 20, wherein the extract is prepared from a plant (i) selected from the group of plant families consisting of Rubiaceae, Verbenaceae, Bignoniaceae, Rhamnaceae, Polygonaceae, Leguminosae, Scropulariaceae, Fabaceae, and Liliaceae; or (ii) selected from the group of plant genera consisting of Rubia; Galium; Rhamnus; Ventilago; Rheum; Rumex; Polygonum; Cassia; Senna; Andira, and Aloe; preferably Rubia and Galium.
25. The method according to claim 20, wherein the extract is prepared from: (i) a plant selected from the group consisting of Galium abaujense Borbás; Galium abruptorum Pomel; Galium absurdum Krendl; Galium achurense Grossh.; Galium acrophyum Hochst. ex Chiov.; Galium acuminatum Ball; Galium acutum Edgew.; Galium adhaerens Boiss. & Balansa; Galium advenum Krendl; Galium aegeum (Stoj. & Kitam.) Ancev; Galium aetnicum Biv.; Galium afropusillum Ehrend.; Galium agrophilum Krendl; Galium aladaghense Parolly; Galium xalbertii Rouy (hybrid from Galium boreale x Galium verum; Galium albescens Hook. f.; Galium album Mill.; Galium album Mill. subsp. album; Galium album subsp. amani Ehrend. & Schönb.-Tem.; Galium album subsp. prusense (K. Koch) Ehrend. & Krendl; Galium album subsp. pycnotrichum (Haw. ex Schult. & Schult. f.) Krendl.; Galium album subsp. suberectum (Klokov) Michalk.; Galium amatymbicum Eckl. & Zeyh.; Galium amblyophyllum Schrenk; Galium amorginum Halácsy; Galium andrewsii A. Gray; Galium andringitrense Homolle ex Puff; Galium anfractum Sommier & Levier; Galium anguineum Ehrend. & Schönb.-Tem.; Galium angulosum A. Gray; Galium angustifolium Nutt.; Galium angustissimum (Hausskn. ex Bornm.) Ehrend.; Galium anisophyllon Vill.; Galium ankaratrense Homolle ex Puff; Galium antarcticum Hook. f.; Galium antitauricum Ehrend.; Galium antuneziae Dempster; Galium aparine L.; Galium aparinoides Forssk.; Galium aragonesii Sennen; Galium araucanum Phil.; Galium arenarium Loisel.; Galium arequipicum Dempster; Galium aretioides Boiss.; Galium argense Dempster & Ehrend.; Galium aristatum L.; Galium arkansanum A. Gray; Galium armenum Schanzer; Galium ascendens Willd. ex Spreng.; Galium aschenbornii Schauer; Galium asparagifolium Boiss. & Heldr.; Galium asperifolium Wall.; Galium asperuloides Edgew.; Galium asprellum Michx.; Galium atherodes Spreng.; Galium atlanticum Pomel; Galium aucheri Boiss.; Galium auratum Klokov; Galium australe DC.; Galium austriacum Jacq.; Galium avascense Krendl; Galium azerbayjanicum Ehrend. & Schönb.-Tem.; Galium azuayicum Dempster; Galium babadaghense Y1ld.; Galium baeticum (Rouy) Ehrend. & Krendl; Galium baghlanense Ehrend. & Schönb.-Tem.; Galium baillonii Brandza; Galium baldense Spreng.; Galium baldensiforme Hand.-Mazz.; Galium balearicum Brig.; Galium x barcinonense Sennen (Galium lucidum x Galium maritimum); Galium basalticum Ehrend. & Schönb.-Tem.; Galium baytopianum Ehrend. & Schönb.-Tem.; Galium beckhausianum G. H. Loos; Galium belizianum Ortega Oliv., Devesa & Rodr. Riaño; Galium bellatulum Klokov; Galium bermudense L.; Galium bifolium S. Watson; Galium bigeminum Griseb.; Galium binifolium N. A. Wakef.; Galium blinii H. Lév.; Galium boissierianum (Steud.) Ehrend. & Krendl; Galium bolanderi A. Gray; Galium boreale L.; Galium boreoaethiopicum Puff; Galium bornmuelleri Hausskn. ex Bornm.; Galium bourgaeanum Coss. ex Batt.; Galium boyacanum Dempster; Galium brachyphyllum Schult.; Galium bracteatum Boiss.; Galium bredasdorpense Puff; Galium brenanii Ehrend. & Verdc.; Galium brevifolium Sm.; Galium breviramosum Krendl; Galium brockmannii Brig.; Galium broterianum Boiss. & Reut.; Galium brunneum Munby; Galium bryoides Merr. & L. M. Perry; Galium buchtienii Dempster; Galium x buekkense Hulják (Galium abaujense x Galium vernum); Galium bullatum Lipsky; Galium bulliforme I. Thomps.; Galium bungei Steud.; Galium bungoniense I. Thomps.; Galium buschiorum Mikheev; Galium bussei K. Schum. & K. Krause; Galium buxifolium Greene; Galium cajamarcense Dempster; Galium californicum Hook. & Am.; Galium caminianum Schult.; Galium campanelliferum Ehrend. & Schönb.-Tem.; Galium campylotrichum Nazim. & Ehrend.; Galium canescens Kunth; Galium cankiriense Y1ld.; Galium canum Req. ex DC.; Galium canum subsp. antalyense Ehrend.; Galium canum Req. ex DC. subsp. canum, Galium canum subsp. ovatum Ehrend.; Galium canum subsp. ulukislaense Y1ld.; Galium capense Thunb.; Galium capitatum Bory & Chaub.; Galium cappadocicum Boiss.; Galium caprarium Natali; Galium capreum Krendl; Galium carmenicola Dempster; Galium x carmineum Beauverd (Galium anisophyllon x Galium pumilum x Galium rubrum).; Galium carterae Dempster; Galium caspicum Steven; Galium cassium Boiss.; Galium catalinense A. Gray; Galium x centroniae Cariot (Galium pumilum x Galium rubrum); Galium ceratoamanianum Ehrend.; Galium ceratocarpon Boiss.; Galium ceratophylloides Hook. f.; Galium ceratopodum Boiss.; Galium cespitosum Lam.; Galium chaetopodum Rech. f.; Galium chekiangense Ehrend.; Galium chloroionanthum K. Schum.; Galium chloroleucum Fisch. & C. A. Mey.; Galium ciliare Hook. f.; Galium cilicicum Boiss.; Galium cinereum All.; Galium circae Krendl; Galium circaezans Michx.; Galium clausonis Pomel; Galium clementis Eastw.; Galium cliftonsmithii (Dempster) Dempster & Stebbins; Galium collomiae J. T. Howell; Galium coloradoense W. Wight; Galium comberi Dempster; Galium cometerhizon Lapeyr.; Galium compactum Ehrend. & McGill.; Galium concatenatum Coss.; Galium concinnum Torr. & A. Gray; Galium confertum Royle ex Hook. f.; Galium conforme Krendl; Galium consanguineum Boiss.; Galium coriaceum Bunge; Galium cornigerum Boiss. & Hausskn.; Galium coronadoense Dempster; Galium correllii Dempster; Galium corsicum Spreng.; Galium corymbosum Ruiz & Pay.; Galium cossonianum Jafri; Galium cotinoides Cham. & Schltdl.; Galium cracoviense Ehrend.; Galium crassifolium W. C. Chen; Galium craticulatum R. R. Mill; Galium crespianum Rodr.; Galium cryptanthum Hemsl.; Galium curvihirtum Ehrend. & McGill.; Galium cuspidulatum Miq.; Galium cyllenium Boiss. & Heldr.; Galium czerepanovii Pobed.; Galium dahuricum Turcz. ex Ledeb.; Galium davisii Ehrend.; Galium debile Desv.; Galium decorum Krendl; Galium decumbens (Ehrend.) Ehrend. & Schönb.-Tem.; Galium degenii Bald. ex Degen; Galium deistelii K. Krause; Galium delicatulum Boiss. & Hohen.; Galium demissum Boiss.; Galium dempsterae B. L. Turner; Galium densum Hook. f.; Galium denticulatum Bartl. ex DC.; Galium desereticum Dempster & Ehrend.; Galium diabolense Dempster; Galium dieckii Bornm.; Galium diffusoramosum Dempster & Ehrend.; Galium x digeneum A. Kern. (Galium sylvaticum x Galium verum); Galium diphyllum (K. Schum.) Dempster; Galium diploprion Boiss. & Hohen.; Galium divaricatum Pourr. ex Lam.; Galium domingense Iltis; Galium dumosum Boiss.; Galium duthiei R. Bhattacharjee; Galium echinocarpum Hayata; Galium ecuadoricum Dempster; Galium x effulgens Beck (Galium lucidum x Galium verum); Galium ehrenbergii Boiss.; Galium elbursense Bornm. & Gauba; Galium elegans Wall. ex Roxb.; Galium elongatum C. Presl; Galium emeryense Dempster & Ehrend.; Galium ephedroides Willk; Galium equisetoides (Cham. & Schltdl.) Standl.; Galium ericoides Lam.; Galium eriocarpum Bartl. ex DC.; Galium eruptivum Krendl; Galium erythrorrhizon Boiss. & Reut.; Galium espiniacicum Dempster; Galium estebanii Sennen; Galium exaltatum Krendl; Galium exile Hook. f.; Galium exstipulatum P. H. Davis; Galium exsurgens Ehrend. & Schönb.-Tem.; Galium extensum Krendl; Galium falconers R. Bhattacharjee; Galium fendleri A. Gray; Galium ferrugineum K. Krause; Galium festivum Krendl; Galium x fictum E. G. Camus (=Galium glaucum x Galium mollugo); Galium filipes Rydb.; Galium firmum Tausch; Galium fissurense Ehrend. & Schönb.-Tem.; Galium fistulosum Sommier & Levier; Galium flavescens Borbás ex Simonk.; Galium flaviflorum (Trautv.) Mikheev; Galium floribundum Sm.; Galium foliosum Munby ex Burnat & Barbey; Galium fontanesianum Pomel; Galium formosense Ohwi; Galium forrestii Diels; Galium fosbergii Dempster; Galium friedrichii N. Torres & al.; Galium fruticosum Willd.; Galium fuegianum Hook. f.; Galium fuscum M. Martens & Galeotti; Galium galapagoense Wiggins; Galium galiopsis (Hand.-Mazz.) Ehrend.; Galium gaudichaudii DC.; Galium geminiflorum Lowe; Galium ghilanicum Stapf; Galium gilliesii Hook. & Arn.; Galium glaberrimum Hemsl.; Galium glabrescens (Ehrend.) Dempster & Ehrend.; Galium glabriusculum Ehrend.; Galium glaciale K. Krause; Galium glandulosum Hand.-Mazz.; Galium glaucophyllum Em. Schmid; Galium glaucum L.; Galium globuliferum Hub.-Mor. & Reese; Galium gracilicaule Bacigalupo & Ehrend.; Galium graecum L.; Galium grande McClatchie; Galium grayanum Ehrend.; Galium gymnopetalum Ehrend. & Schönb.-Tem.; Galium hainesii Schönb.-Tem.; Galium hallii Munz & I. M. Johnst.; Galium hardhamae Dempster; Galium hatschbachii Dempster; Galium haussknechtii Ehrend.; Galium heldreichii Halácsy; Galium hellenicum Krendl; Galium hexanarium Knjaz.; Galium hierochuntinum Bornm.; Galium hierosolymitanum L.; Galium hilendiae Dempster & Ehrend.; Galium x himmelbaurianum (Ronniger) Soó (Galium humifusum x Galium verum); Galium hintoniorum B. L. Turner; Galium hirtiflorum Req. ex DC.; Galium hirtum Lam.; Galium hoffmeisteri (Klotzsch) Ehrend. & Schönb.-Tem. ex R. R. Mill; Galium homblei De Wild.; Galium huancavelicum Dempster; Galium hubermorathii Ehrend. & Schönb.-Tem.; Galium humifusum M. Bieb.; Galium humile Cham. & Schltdl.; Galium x hungaricum A. Kern. (Galium mollugo x Galium schultesii); Galium hupehense Pamp.; Galium x huteri A. Kern. (Galium laevigatum x Galium lucidum); Galium hypocarpium (L.) Endl. ex Griseb.; Galium hypotrichium A. Gray; Galium hypoxylon Ehrend. & Schönb.-Tem.; Galium hyrcanicum C. A. Mey; Galium hystricocarpum Greenm.; Galium idubedae (Pau & Debeaux) Pau ex Ehrend.; Galium iltisii Dempster; Galium incanum Sm.; Galium incanum subsp. centrale Ehrend.; Galium incanum subsp. creticum Ehrend.; Galium incanum subsp. elatius (Boiss.) Ehrend.; Galium incanum Sm. subsp. incanum; Galium incanum subsp. libanoticum Ehrend.; Galium incanum subsp. pseudocornigerum Ehrend.; Galium inconspicuum Phil.; Galium incrassatum Halácsy; Galium incurvum Sibth. & Sm.; Galium innocuum Miq.; Galium insulare Krendl; Galium intermedium Schult., Syn.; Galium schultesii Vest; Galium aristatum subsp. schultesii (Vest) Nyman); Galium intricatum Margot & Reut.; Galium ionicum Krendl; Galium iranicum Hausskn. ex Bornm.; Galium irinae Pachom.; Galium isauricum Ehrend. & Schönb.-Tem.; Galium x jansenii Kloos (Galium sylvaticum x Galium mollugo); Galium japonicum Makino; Galium x jarynae Wol. (Galium aristatum x Galium mollugo); Galium javalambrense López Udias, Mateo & M. B. Crespo; Galium javanicum Blume; Galium jemense Kotschy; Galium jepsonii Hilend & J. T. Howell; Galium johnstonii Dempster & Stebbins; Galium jolyi Batt.; Galium judaicum Boiss.; Galium jungermannioides Boiss.; Galium junghuhnianum Miq.; Galium juniperinum Standl.; Galium kaganense R. Bhattacharjee; Galium kahelianum Deflers; Galium kamtschaticum Steller ex Schult.; Galium karakulense Pobed.; Galium karataviense (Pavlov) Pobed.; Galium kasachstanicum Pachom.; Galium kenyanum Verdc.; Galium kerneri Degen & Dörfl.; Galium khorasanense Griff.; Galium kikumuyura Ohwi; Galium killipii Dempster & Ehrend.; Galium kinuta Nakai & H. Hara.; Galium kitaibelianum Schult.; Galium x kondratjukii Ostapko (Galium cincinnatum x Galium tomentosum); Galium kuetzingii Boiss. & Buhse; Galium kunmingense Ehrend.; Galium kurdicum Boiss. & Hohen.; Galium labradoricum (Wiegand) Wiegand; Galium laconicum Boiss. & Heldr.; Galium lacrimiforme Dempster; Galium laevigatum L.; Galium lahulense Ehrend. & Schönb.-Tem.; Galium lanceolatum (Ton. & A. Gray) Torr.; Galium lanuginosum Lam.; Galium x lanulosum Ostapko (Galium humifusum x Galium tomentosum); Galium lasiocarpum Boiss.; Galium latifolium Michx.; Galium latoramosum Clos; Galium leiocarpum I. Thomps.; Galium leptogonium I. Thomps.; Galium leptum Phil.; Galium libanoticum Ehrend.; Galium lilloi Hicken; Galium x lindbergii Giraudias; Galium linearifolium Turcz.; Galium liratum N. A. Wakef.; Galium litorale Guss.; Galium lovcense Urum.; Galium lucidum All.; Galium macedonicum Krendl; Galium magellanicum Hook. f.; Galium magellense Ten.; Galium magnifolium (Dempster) Dempster; Galium mahadivense G. Singh; Galium malickyi Krendl.; Galium mandonii Britton; Galium maneauense P. Royen; Galium marchandii Roem. & Schult.; Galium margaceum Ehrend. & Schönb.-Tem.; Galium margaritaceum A. Kern.; Galium maritimum L.; Galium martirense Dempster & Stebbins; Galium masafueranum Skottsb.; Galium matthewsii A. Gray; Galium maximowiczii (Kom.) Pobed.; Galium mechudoense Dempster; Galium megacyttarion R. R. Mill; Galium megalanthum Boiss.; Schweizer Labkraut (Galium megalospermum All.); Galium megapotamicum Spreng.; Galium melanantherum Boiss.; Galium meliodorum (Beck) Fritsch; Galium membranaceum Ehrend.; Galium mexicanum Kunth; Galium microchiasma Gilli; Galium microlobum I. Thomps.; Galium microphyllum A. Gray; Galium migrans Ehrend. & McGill.; Galium minutissimum T. Shimizu; Galium minutulum Jord.; Galium mirum Rech. f.; Galium mite Boiss. & Hohen.; Galium moldavicum (Dobrocz.) Franco; Galium mollugo L.; Galium monachinii Boiss. & Heldr.; Galium monasterium Krendl; Galium monticolum Sond.; Galium montis-arerae Merxm. & Ehrend.; Galium moralesianum Ortega Oliv. & Devesa; Galium moranii Dempster; Galium morii Hayata; Galium mucroniferum Sond.; Galium muelleri (K. Schum.) Dempster; Galium multiflorum Kellogg; Galium munzii Hilend & J. T. Howell; Galium murale (L.) All.; Galium murbeckii Maire; Galium muricatum W. Wight; Galium x mutabile Besser (Galium mollugo x Galium verum); Galium nabelekii Ehrend. & Schönb.-Tem.; Galium nakaii Kudo; Galium nankotaizanum Ohwi; Galium x neglectum Le Gall ex Gren. & Godr. (Galium album x Galium arenarium); Galium nepalense Ehrend. & Schönb.-Tem.; Galium nevadense Boiss. & Reut.; Galium nigdeense Y1ld.; Galium nigricans Boiss.; Galium nigroramosum (Ehrend.) Dempster; Galium nolitangere Ball; Galium noricum Ehrend.; Galium normanii Dahl; Galium novoguineense Diels; Galium noxium (A. St.-Hil.) Dempster; Galium numidicum Pomel; Galium nupercreatum Popov; Galium nuttallii A. Gray; Galium obliquum Vill.; Galium obovatum Kunth; Galium obtusum Bigelow; Galium octonarium (Klokov) Pobed.; Galium odoratum (L.) Scop.; Galium oelandicum Ehrend.; Galium olgae Klokov; Galium olivetorum Le Houér; Galium olympicum Boiss.; Galium ophiolithicum Krendl; Galium oreganum Britton; Galium oreophilum Krendl; Galium oresbium Greenm.; Galium orizabense Hemsl.; Galium oshtenicum Ehrend. & Schanzer ex Mikheev; Galium ossirwaense K. Krause; Galium ostenianum (Standl.) Dempster; Galium ovalleanum Phil.; Galium pabulosum Sommier & Levier; Galium palaeoitalicum Ehrend.; Galium palustre L.; Galium pamiroalaicum Pobed.; Galium pamphylicum Boiss. & Heldr.; Galium paniculatum (Bunge) Pobed.; Galium papilliferum Ehrend. & Schönb.-Tem.; Galium papillosum Lapeyr.; Galium papuanum Wernham; Galium paradoxum Maxim.; Galium parishii Hilend & J. T. Howell; Galium parisiense L.; Galium parvulum Hub.-Mor. ex Ehrend. & Schönb.-Tem.; Galium paschale Forssk.; Galium pastorale Krendl; Galium patzkeanum G. H. Loos; Galium peloponnesiacum Ehrend. & Krendl; Galium penduliflorum Boiss.; Galium pendulum Greenm.; Galium penicillatum Boiss.; Galium pennellii Dempster; Galium peplidifolium Boiss.; Galium perralderi Coss.; Galium peruvianum Dempster & Ehrend.; Galium pestalozzae Boiss.; Galium petrae Oliv. ex Hart; Galium philippianum Dempster; Galium philippinense Merr.; Galium philistaeum Boiss.; Galium pilosum Aiton; Galium pisiferum Boiss.; Galium pisoderium Krendl; Galium platygalium (Maxim.) Pobed.; Galium plumosum Rusby; Galium poiretianum Ball; Galium pojarkovae Pobed.; Galium polyacanthum (Baker) Puff; Galium polyanthum I. Thomps.; Galium x pomeranicum Retz. (Galium album x Galium verum); Galium porrigens Dempster; Galium praemontanum Mardal.; Galium praetermissum Greenm.; Galium x pralognense Beauverd (Galium pumilum x Galium verum); Galium prattii Cufod.; Galium pringlei Greenm.; Galium problematicum (Ehrend.) Ehrend. & Schönb.-Tem.; Galium procurrens Ehrend.; Galium productum Lowe; Galium x prolazense Nyár. (Galium album x Galium flavescens); Galium proliferum A. Gray; Galium propinquum A. Cunn.; Galium pruinosum Boiss.; Galium pseudoaristatum Schur; Galium x pseudoboreale Klokov (Galium boreale x Galium rubioides); Galium pseudocapitatum Hub.-Mor. ex Ehrend. & Schönb.-Tem.; Galium pseudohelveticum Ehrend.; Galium pseudokurdicum (Ehrend.) Schönb.-Tem.; Galium pseudorivale Tzvelev; Galium pseudotriflorum Dempster & Ehrend.; Galium psilocladum Ehrend.; Galium pterocarpum Ehrend.; Galium pulvinatum Boiss.; Galium pumilio Standl.; Galium pumilum Murray; Galium pusillosetosum H. Hara; Galium pusillum L.; Galium pyrenaicum Gouan; Galium qaradaghense Schönb.-Tem.; Galium x querceticola Wol. (Galium abaujense subsp. polonicum x Galium intermedium); Galium quichense Dempster; Galium radulifolium Ehrend. & Schönb.-Tem.; Galium ramboi Dempster; Galium rebae R. R. Mill; Galium reiseri Halácsy; Galium x retzii Bouchard (Galium papillosum x Galium verum); Galium rhodopeum Velen.; Galium richardianum (Gillies ex Hook. & Am.) Endl. ex Walp.; Galium rigidifolium Krendl; Galium rivale (Sibth. & Sm.) Griseb.; Galium roddii Ehrend. & McGill.; Galium rosellum (Boiss.) Boiss. & Reut.; Galium rotundifolium L.; Galium rourkei Puff; Galium rubidiflorum Dempster; Galium rubioides L.; Galium rubrum L.; Galium runcinatum Ehrend. & Schönb.-Tem.; Galium rupifragum Ehrend.; Galium ruwenzoriense (Cortesi) Ehrend.; Galium rzedowskii Dempster; Galium sacrorum Krendl; Galium saipalense Ehrend. & Schönb.-Tem.; Galium salsugineum Krylov & Serg.; Galium salwinense Hand.-Mazz.; Galium samium Krendl; Galium samuelssonii Ehrend.; Galium saturejifolium Trevir.; Galium saurense Litv.; Galium saxatile L., Syn.: Galium harcynicum Weigel, Galium pawlowskii Kucowa, Galium pumilum subsp. saxatile (L.) Dostál; Galium saxosum (Chaix) Breistr.; Galium scabrelloides Puff; Galium scabrellum K. Schum.; Galium scabrifolium (Boiss.) Hausskn.; Galium scabrum L.; Galium schlumbergeri Boiss.; Galium x schmidelyi Chenevard & W. Wolf (Galium mollugo x Galium rubrum); Galium schmidii Arrigoni; Galium x schneebergense Ronniger (Galium anisophyllon x Galium meliodorum); Galium schoenbeck-temesyae Ehrend.; Galium scioanum Chiov.; Galium scopulorum Schönb.-Tem.; Galium seatonii Greenm.; Galium sellowianum (Cham.) Walp.; Galium semiamictum Klokov; Galium serpenticum Dempster; Galium serpylloides Royle ex Hook. f.; Galium setaceum Lam.; Galium setuliferum Ehrend. & Schönb.-Tem.; Galium shanense R. Bhattacharjee; Galium shepardii Post; Galium shepherdii Jung-Mend.; Galium sichuanense Ehrend.; Galium sidamense Chiov. ex Chiarugi; Galium sieheanum Ehrend.; Galium simense Fresen.; Galium similii Pavlov; Galium sinaicum (Delile ex Decne.) Boiss.; Galium smithreitzii Dempster; Galium sojakii Ehrend. & Schönb.-Tem.; Galium songaricum Schrenk; Galium sorgerae Ehrend. & Schönb.-Tem.; Galium sparsiflorum W. Wight; Galium spathulatum I. Thomps.; Galium speciosum Krendl; Galium sphagnophilum (Greenm.) Dempster; Galium spurium L.; Galium stellatum Kellogg; Galium stenophyllum Baker; Galium stepparum Ehrend. & Schönb.-Tem.; Galium sterneri Ehrend.; Galium subfalcatum Nazim. & Ehrend.; Galium subnemorale Klokov & Zaver.; Galium subtrifidum Reinw. ex Blume; Galium subtrinervium Ehrend. & Schönb.-Tem.; Galium subuliferum Sommier & Levier; Galium subvelutinum (DC.) K. Koch; Galium subvillosum Sond.; Galium sudeticum Tausch; Galium suecicum (Sterner) Ehrend.; Galium suffruticosum Hook. & Am. (Rubia margaritifera Reiche); Galium sungpanense Cufod.; Galium surinamense Dempster; Galium sylvaticum L.; Galium taiwanense Masam.; Galium takasagomontanum Masam.; Galium talaveranum Ortega Oliv. & Devesa; Galium tanganyikense Ehrend. & Verdc.; Galium tarokoense Hayata; Galium taygeteum Krendl; Galium tendae Rchb. f.; Galium tenuissimum M. Bieb.; Galium terraereginae Ehrend. & McGill.; Galium tetraphyllum Nazim. & Ehrend.; Galium texense A. Gray; Galium thasium Stoj. & Kitanov; Galium thiebautii Ehrend.; Galium thracicum Krendl; Galium thunbergianum Eckl. & Zeyh.; Galium thymifolium Boiss. & Heldr.; Galium tianschanicum Popov; Galium timeroyi Jord.; Galium tinctorium L.; Galium tmoleum Boiss.; Galium tokyoense Makino; Galium tolosianum Boiss. & Kotschy; Galium tomentosum Thunb.; Galium tortumense Ehrend. & Schönb.-Tem.; Galium transcarpaticum Stojko & Tasenk.; Galium trichocarpum DC.; Galium tricornutum Dandy; Galium trifidum L.; Galium trifloriforme Kom.; Galium triflorum Michx.; Galium trilobum Colenso; Galium trinioides Pomel; Galium trojanum Ehrend.; Galium truniacum (Ronniger); Galium tubiflorum Ehrend.; Galium tuncelianum Y1ld; Galium tunetanum Lam.; Galium turgaicum Knjaz.; Galium turkestanicum Pobed.; Galium tyraicum Klokov; Galium uliginosum L.; Galium uncinulatum DC.; Galium undulatum Puff; Galium uniflorum Michx.; Galium uruguayense Bacigalupo; Galium valantioides M. Bieb.; Galium valdepilosum Heinr. Braun; Galium valentinum Lange; Galium vartanii Grossh.; Galium vassilczenkoi Pobed.; Galium velenovskyi Ancev; Galium verrucosum Huds.; Galium verticillatum Danthoine ex Lam.; Galium verum L.; Galium verum subsp. asiaticum (Nakai) T. Yamaz.; Galium verum subsp. glabrescens Ehrend.; Galium verum L. subsp. verum; Galium verum subsp. wirtgenii (F. W. Schultz) Oborny (Syn. Galium wirtgenii F. W. Schultz); Galium x viciosorum Sennen & Pau (Galium maritimum x Galium verum); Galium vile (Cham. & Schltdl.) Dempster; Galium violaceum Krendl; Galium virgatum Nutt.; Galium viridiflorum Boiss. & Reut.; Galium viscosum Vahl; Galium volcanense Dempster; Galium volhynicum Pobed.; Galium watsonii (A. Gray) A. Heller; Galium weberbaueri K. Krause; Galium wendelboi Ehrend. & Schönb.-Tem.; Galium werdermannii Standl.; Galium wigginsii Dempster; Galium wrightii A. Gray; Galium xeroticum (Klokov) Pobed.; Galium xylorrhizum Boiss. & A. Huet; Galium yunnanense H. Hara & C. Y. Wu; Galium zabense Ehrend.; Rubia agostinhoi Dans. & P. Silva; Rubia aitchisonii Deb & Malick; Rubia alaica Pachom.; Rubia alata Wall.; Rubia albicaulis Boiss.; Rubia angustisissima Wall. ex G. Don; Rubia argyi (H. Lév. & Vaniot) Hara ex Lauener, Syn.; Rubia akane Nakai, Rubia chekiangensis Deb, Rubia nankotaizana (Masam); Rubia atropurpurea Decne.; Rubia austrozhejiangensis Z. P. Lei, Y. Y. Zhou & R. W. Wang; Rubia balearica (Willk.) Porta; Rubia balearica (Willk.) Porta subsp. balearica; Rubia balearica subsp. caespitosa (Font Quer & Marcos) Rosselló, L. Sáez & Mus (Rubia angustifolia var. caespitosa Font Quer & Marcos, Rubia angustifolia subsp. caespitosa (Font Quer & Marcos) Rosselló, Rubia caespitosa (Font Quer & Marcos) Rosselló); Rubia caramanica Bornm.; Rubia charifolia Wall. ex G. Don.; Rubia chinensis Regel & Maack; Rubia chinensis f. chinensis (Rubia chinensis f. mitis (Miq.) Kitag.); Rubia chinensis f. glabrescens (Nakai) Kitag.; Rubia chitralensis Ehrend.; Rubia clematidifolia Blume ex Decne.; Rubia cordifolia L.; Rubia cordifolia subsp. conotricha (Gand.) Verdc.; Rubia cordifolia subsp. cordifolia; Rubia crassipes Collett & Hemsl.; Rubia cretacea Pojark.; Rubia danaensis Danin; Rubia davisiana Ehrend.; Rubia deserticola Pojark.; Rubia discolor Turcz.; Rubia dolichophylla Schrenk; Rubia edgeworthii Hook. f.; Rubia falciformis H. S. Lo; Rubia filiformis F. C. How ex H. S. Lo; Rubia florida Boiss; Rubia garrettii Craib; Rubia gedrosiaca Bornm.; Rubia haematantha Airy Shaw; Rubia hexaphylla (Makino) Makino; Rubia hispidicaulis D. G. Long; Rubia infundibularis Hemsl. & Lace; Rubia jesoensis (Miq.) Miyabe & Kudo; Rubia komarovii Pojark; Rubia krascheninnikovii Pojark; Rubia laevissima Tsckern.; Rubia latipetala H. S. Lo; Rubia laurae (Holmboe) Airy Shaw; Rubia laxiflora Gontsch.; Rubia linii J. M. Chao; Rubia magna P. G. Xiao; Rubia mandersii Collett & Hemsl.; Rubia manjith Roxb. ex Fleming; Rubia maymanensis Ehrend. & Schönb.-Tem; Rubia membranacea Diels; Rubia oncotricha Hand.-Mazz.; Rubia oppositifolia Griff.; Rubia ovatifolia Z. Ying Zhang ex Q. Lin; Rubia pallida Diels; Rubia pauciflora Boiss.; Rubia pavlovii Bajtenov & Myrz.; Rubia peregrina L.; Rubia petiolaris DC.; Rubia philippinensis Elmer; Rubia pianmaensis R. Li & H. Li; Rubia podantha Diels; Rubia polyphlebia H. S. Lo; Rubia pseudogalium Ehrend.; Rubia pterygocaulis H. S. Lo; Rubia rechingeri Ehrend.; Rubia rezniczenkoana Litv.; Rubia rigidifolia Pojark.; Rubia rotundifolia Banks & Sol.; Rubia salicifolia H. S. Lo; Rubia schugnanica B. Fedtsch. ex Pojark.; Rubia schumanniana E. Pritz.; Rubia siamensis Craib; Rubia sikkimensis Kurz; Rubia sylvatica (Maxim.) Nakai; Rubia tatarica (Trevir.) F. Schmidt; Rubia tenuifolia d'Urv.; Rubia tenuifolia subsp. brachypoda (Boiss.) Ehrend. & Schönb.-Tem.; Rubia tenuifolia subsp. doniettii (Griseb.) Ehrend. & Schönb.-Tem.; Rubia tenuifolia subsp. tenuifolia; Rubia tenuissima fined. (Syn.: Rubia tenuis H. S. Lonom. illeg.); Rubia thunbergii DC.; Rubia tibetica Hook. f.; Rubia tinctorum L.; Rubia transcaucasica Grossh.; Rubia trichocarpa H. S. Lo; Rubia truppeliana Loes.; Rubia wallichiana Decne.; and Rubia yunnanensis Diels; preferably a plant selected from Galium aparine, Galium verum and Rubia cardifolia L.; (ii) from a fungus of a fungal genus selected from the group consisting of: Alternaria genus; Aspergillus genus, preferably Aspergillus chevalieri, Aspergillus glaucus and Aspergillus fumigatus; Boletus genus, preferably comprising Boletol and Carminic acid; Cortinarius genus; Curvularia genus; Eurotium genus; Fusarium genus; Haloresellinia genus; Helminthosporium genus, preferably H. cynodontis, H. catenarium and H. triticivulgaris; Microshaeropsis genus; Monodictys genus; Nigrospora genus; Paecilomyces genus; Penicillium genus, preferably P. cyclopium, P. citreo-roseum, P. carmine-violaceum, P. roseo-purpureum and P. cyclopium; Phomopsis; Preussia genus, preferably Pressuia multispora (Saito et Minoura) Cain; Valsaria genus, preferably Valsaria rubricosa, preferably comprising Papulosin, valsarin; Talaromyces genus, preferably Talaromyces avellaneus (Thom et Turreson) C. R. Benjamin; or (iii) from a fungus of a Lichen genus, preferably a Lichen genus selected from the group consisting of Xanthoria genus, preferably Xanthoria parietina; Lecidella genus, preferably Lecidella asema; Lasallia genus, preferably Lasallia papulose var. rubiginosa; Trypethelium genus, preferably Trypethelium cruentum (Pyrenula cruenta).
26. The method according to claim 24, wherein the extract is prepared from: (i) a plant selected from the group consisting of Galium abaujense Borbás; Galium abruptorum Pomel; Galium absurdum Krendl; Galium achurense Grossh.; Galium acrophyum Hochst. ex Chiov.; Galium acuminatum Ball; Galium acutum Edgew.; Galium adhaerens Boiss. & Balansa; Galium advenum Krendl; Galium aegeum (Stoj. & Kitam.) Ancev; Galium aetnicum Biv.; Galium afropusillum Ehrend.; Galium agrophilum Krendl; Galium aladaghense Parolly; Galium xalbertii Rouy (hybrid from Galium boreale x Galium verum; Galium albescens Hook. f.; Galium album Mill.; Galium album Mill. subsp. album; Galium album subsp. amani Ehrend. & Schönb.-Tem.; Galium album subsp. prusense (K. Koch) Ehrend. & Krendl; Galium album subsp. pycnotrichum (Haw. ex Schult. & Schult. f.) Krendl.; Galium album subsp. suberectum (Klokov) Michalk.; Galium amatymbicum Eckl. & Zeyh.; Galium amblyophyllum Schrenk; Galium amorginum Halácsy; Galium andrewsii A. Gray; Galium andringitrense Homolle ex Puff; Galium anfractum Sommier & Levier; Galium anguineum Ehrend. & Schönb.-Tem.; Galium angulosum A. Gray; Galium angustifolium Nutt.; Galium angustissimum (Hausskn. ex Bornm.) Ehrend.; Galium anisophyllon Vill.; Galium ankaratrense Homolle ex Puff; Galium antarcticum Hook. f.; Galium antitauricum Ehrend.; Galium antuneziae Dempster; Galium aparine L.; Galium aparinoides Forssk.; Galium aragonesii Sennen; Galium araucanum Phil.; Galium arenarium Loisel.; Galium arequipicum Dempster; Galium aretioides Boiss.; Galium argense Dempster & Ehrend.; Galium aristatum L.; Galium arkansanum A. Gray; Galium armenum Schanzer; Galium ascendens Willd. ex Spreng.; Galium aschenbornii Schauer; Galium asparagifolium Boiss. & Heldr.; Galium asperifolium Wall.; Galium asperuloides Edgew.; Galium asprellum Michx.; Galium atherodes Spreng.; Galium atlanticum Pomel; Galium aucheri Boiss.; Galium auratum Klokov; Galium australe DC.; Galium austriacum Jacq.; Galium avascense Krendl; Galium azerbayjanicum Ehrend. & Schönb.-Tem.; Galium azuayicum Dempster; Galium babadaghense Y1ld.; Galium baeticum (Rouy) Ehrend. & Krendl; Galium baghlanense Ehrend. & Schönb.-Tem.; Galium baillonii Brandza; Galium baldense Spreng.; Galium baldensiforme Hand.-Mazz.; Galium balearicum Briq.; Galium x barcinonense Sennen (Galium lucidum x Galium maritimum); Galium basalticum Ehrend. & Schönb.-Tem.; Galium baytopianum Ehrend. & Schönb.-Tem.; Galium beckhausianum G. H. Loos; Galium belizianum Ortega Oliv., Devesa & Rodr. Riaño; Galium bellatulum Klokov; Galium bermudense L.; Galium bifolium S. Watson; Galium bigeminum Griseb.; Galium binifolium N. A. Wakef.; Galium blinii H. Lév.; Galium boissierianum (Steud.) Ehrend. & Krendl; Galium bolanderi A. Gray; Galium boreale L.; Galium boreoaethiopicum Puff; Galium bornmuelleri Hausskn. ex Bornm.; Galium bourgaeanum Coss. ex Batt.; Galium boyacanum Dempster; Galium brachyphyllum Schult.; Galium bracteatum Boiss.; Galium bredasdorpense Puff; Galium brenanii Ehrend. & Verdc.; Galium brevifolium Sm.; Galium breviramosum Krendl; Galium brockmannii Briq.; Galium broterianum Boiss. & Reut.; Galium brunneum Munby; Galium bryoides Merr. & L. M. Perry; Galium buchtienii Dempster; Galium x buekkense Hulják (Galium abaujense x Galium vernum); Galium bullatum Lipsky; Galium bulliforme I. Thomps.; Galium bungei Steud.; Galium bungoniense I. Thomps.; Galium buschiorum Mikheev; Galium bussei K. Schum. & K. Krause; Galium buxifolium Greene; Galium cajamarcense Dempster; Galium californicum Hook. & Am.; Galium caminianum Schult.; Galium campanelliferum Ehrend. & Schönb.-Tem.; Galium campylotrichum Nazim. & Ehrend.; Galium canescens Kunth; Galium cankiriense Y1ld.; Galium canum Req. ex DC.; Galium canum subsp. antalyense Ehrend.; Galium canum Req. ex DC. subsp. canum; Galium canum subsp. ovatum Ehrend.; Galium canum subsp. ulukislaense Y1ld.; Galium capense Thunb.; Galium capitatum Bory & Chaub.; Galium cappadocicum Boiss.; Galium caprarium Natali; Galium capreum Krendl; Galium carmenicola Dempster; Galium x carmineum Beauverd (Galium anisophyllon x Galium pumilum x Galium rubrum).; Galium carterae Dempster; Galium caspicum Steven; Galium cassium Boiss.; Galium catalinense A. Gray; Galium x centroniae Cariot (Galium pumilum x Galium rubrum); Galium ceratoamanianum Ehrend.; Galium ceratocarpon Boiss.; Galium ceratophylloides Hook. f.; Galium ceratopodum Boiss.; Galium cespitosum Lam.; Galium chaetopodum Rech. f.; Galium chekiangense Ehrend.; Galium chloroionanthum K. Schum.; Galium chloroleucum Fisch. & C. A. Mey.; Galium ciliare Hook. f.; Galium cilicicum Boiss.; Galium cinereum All.; Galium circae Krendl; Galium circaezans Michx.; Galium clausonis Pomel; Galium clementis Eastw.; Galium cliftonsmithii (Dempster) Dempster & Stebbins; Galium collomiae J. T. Howell; Galium coloradoense W. Wight; Galium comberi Dempster; Galium cometerhizon Lapeyr.; Galium compactum Ehrend. & McGill.; Galium concatenatum Coss.; Galium concinnum Ton. & A. Gray; Galium confertum Royle ex Hook. f.; Galium conforme Krendl; Galium consanguineum Boiss.; Galium coriaceum Bunge; Galium cornigerum Boiss. & Hausskn.; Galium coronadoense Dempster; Galium correllii Dempster; Galium corsicum Spreng.; Galium corymbosum Ruiz & Pay.; Galium cossonianum Jafri; Galium cotinoides Cham. & Schltdl.; Galium cracoviense Ehrend.; Galium crassifolium W. C. Chen; Galium craticulatum R. R. Mill; Galium crespianum Rodr.; Galium cryptanthum Hemsl.; Galium curvihirtum Ehrend. & McGill.; Galium cuspidulatum Miq.; Galium cyllenium Boiss. & Heldr.; Galium czerepanovii Pobed.; Galium dahuricum Turcz. ex Ledeb.; Galium davisii Ehrend.; Galium debile Desv.; Galium decorum Krendl; Galium decumbens (Ehrend.) Ehrend. & Schönb.-Tem.; Galium degenii Bald. ex Degen; Galium deistelii K. Krause; Galium delicatulum Boiss. & Hohen.; Galium demissum Boiss.; Galium dempsterae B. L. Turner; Galium densum Hook. f.; Galium denticulatum Bartl. ex DC.; Galium desereticum Dempster & Ehrend.; Galium diabolense Dempster; Galium dieckii Bornm.; Galium diffusoramosum Dempster & Ehrend.; Galium x digeneum A. Kern. (Galium sylvaticum x Galium verum); Galium diphyllum (K. Schum.) Dempster; Galium diploprion Boiss. & Hohen.; Galium divaricatum Pourr. ex Lam.; Galium domingense Iltis; Galium dumosum Boiss.; Galium duthiei R. Bhattacharjee; Galium echinocarpum Hayata; Galium ecuadoricum Dempster; Galium x effulgens Beck (Galium lucidum x Galium verum); Galium ehrenbergii Boiss.; Galium elbursense Bornm. & Gauba; Galium elegans Wall. ex Roxb.; Galium elongatum C. Presl; Galium emeryense Dempster & Ehrend.; Galium ephedroides Willk.; Galium equisetoides (Cham. & Schltdl.) Standl.; Galium ericoides Lam.; Galium eriocarpum Bartl. ex DC.; Galium eruptivum Krendl; Galium erythrorrhizon Boiss. & Reut.; Galium espiniacicum Dempster; Galium estebanii Sennen; Galium exaltatum Krendl; Galium exile Hook. f.; Galium exstipulatum P. H. Davis; Galium exsurgens Ehrend. & Schönb.-Tem.; Galium extensum Krendl; Galium falconers R. Bhattacharjee; Galium fendleri A. Gray; Galium ferrugineum K. Krause; Galium festivum Krendl; Galium x fictum E. G. Camus (=Galium glaucum x Galium mollugo); Galium filipes Rydb.; Galium firmum Tausch; Galium fissurense Ehrend. & Schönb.-Tem.; Galium fistulosum Sommier & Levier; Galium flavescens Borbás ex Simonk.; Galium flaviflorum (Trautv.) Mikheev; Galium floribundum Sm.; Galium foliosum Munby ex Burnat & Barbey; Galium fontanesianum Pomel; Galium formosense Ohwi; Galium forrestii Diels; Galium fosbergii Dempster; Galium friedrichii N. Torres & al.; Galium fruticosum Willd.; Galium fuegianum Hook. f.; Galium fuscum M. Martens & Galeotti; Galium galapagoense Wiggins; Galium galiopsis (Hand.-Mazz.) Ehrend.; Galium gaudichaudii DC.; Galium geminiflorum Lowe; Galium ghilanicum Stapf; Galium gilliesii Hook. & Arn.; Galium glaberrimum Hemsl.; Galium glabrescens (Ehrend.) Dempster & Ehrend.; Galium glabriusculum Ehrend.; Galium glaciale K. Krause; Galium glandulosum Hand.-Mazz.; Galium glaucophyllum Em. Schmid; Galium glaucum L.; Galium globuliferum Hub.-Mor. & Reese; Galium gracilicaule Bacigalupo & Ehrend.; Galium graecum L.; Galium grande McClatchie; Galium grayanum Ehrend.; Galium gymnopetalum Ehrend. & Schönb.-Tem.; Galium hainesii Schönb.-Tem.; Galium hallii Munz & I. M. Johnst.; Galium hardhamae Dempster; Galium hatschbachii Dempster; Galium haussknechtii Ehrend.; Galium heldreichii Halácsy; Galium hellenicum Krendl; Galium hexanarium Knjaz.; Galium hierochuntinum Bornm.; Galium hierosolymitanum L.; Galium hilendiae Dempster & Ehrend.; Galium x himmelbaurianum (Ronniger) Soó (Galium humifusum x Galium verum); Galium hintoniorum B. L. Turner; Galium hirtiflorum Req. ex DC.; Galium hirtum Lam.; Galium hoffmeisteri (Klotzsch) Ehrend. & Schönb.-Tem. ex R. R. Mill; Galium homblei De Wild.; Galium huancavelicum Dempster; Galium hubermorathii Ehrend. & Schönb.-Tem.; Galium humifusum M. Bieb.; Galium humile Cham. & Schltdl.; Galium x hungaricum A. Kern. (Galium mollugo x Galium schultesii); Galium hupehense Pamp.; Galium x huteri A. Kern. (Galium laevigatum x Galium lucidum); Galium hypocarpium (L.) Endl. ex Griseb.; Galium hypotrichium A. Gray; Galium hypoxylon Ehrend. & Schönb.-Tem.; Galium hyrcanicum C. A. Mey; Galium hystricocarpum Greenm.; Galium idubedae (Pau & Debeaux) Pau ex Ehrend.; Galium iltisii Dempster; Galium incanum Sm.; Galium incanum subsp. centrale Ehrend.; Galium incanum subsp. creticum Ehrend.; Galium incanum subsp. elatius (Boiss.) Ehrend.; Galium incanum Sm. subsp. incanum; Galium incanum subsp. libanoticum Ehrend.; Galium incanum subsp. pseudocornigerum Ehrend.; Galium inconspicuum Phil.; Galium incrassatum Halácsy; Galium incurvum Sibth. & Sm.; Galium innocuum Miq.; Galium insulare Krendl; Galium intermedium Schult., Syn.; Galium schultesii Vest; Galium aristatum subsp. schultesii (Vest) Nyman); Galium intricatum Margot & Reut.; Galium ionicum Krendl; Galium iranicum Hausskn. ex Bornm.; Galium irinae Pachom.; Galium isauricum Ehrend. & Schönb.-Tem.; Galium x jansenii Kloos (Galium sylvaticum x Galium mollugo); Galium japonicum Makino; Galium x jarynae Wol. (Galium aristatum x Galium mollugo); Galium javalambrense López Udias, Mateo & M. B. Crespo; Galium javanicum Blume; Galium jemense Kotschy; Galium jepsonii Hilend & J. T. Howell; Galium johnstonii Dempster & Stebbins; Galium jolyi Batt.; Galium judaicum Boiss.; Galium jungermannioides Boiss.; Galium junghuhnianum Miq.; Galium juniperinum Standl.; Galium kaganense R. Bhattacharjee; Galium kahelianum Deflers; Galium kamtschaticum Steller ex Schult.; Galium karakulense Pobed.; Galium karataviense (Pavlov) Pobed.; Galium kasachstanicum Pachom.; Galium kenyanum Verdc.; Galium kerneri Degen & Dörfl.; Galium khorasanense Griff.; Galium kikumuyura Ohwi; Galium killipii Dempster & Ehrend.; Galium kinuta Nakai & H. Hara.; Galium kitaibelianum Schult.; Galium x kondratjukii Ostapko (Galium cincinnatum x Galium tomentosum); Galium kuetzingii Boiss. & Buhse; Galium kunmingense Ehrend.; Galium kurdicum Boiss. & Hohen.; Galium labradoricum (Wiegand) Wiegand; Galium laconicum Boiss. & Heldr.; Galium lacrimiforme Dempster; Galium laevigatum L.; Galium lahulense Ehrend. & Schönb.-Tem.; Galium lanceolatum (Ton. & A. Gray) Torr.; Galium lanuginosum Lam.; Galium x lanulosum Ostapko (Galium humifusum x Galium tomentosum); Galium lasiocarpum Boiss.; Galium latifolium Michx.; Galium latoramosum Clos; Galium leiocarpum I. Thomps.; Galium leptogonium I. Thomps.; Galium leptum Phil.; Galium libanoticum Ehrend.; Galium lilloi Hicken; Galium x lindbergii Giraudias; Galium linearifolium Turcz.; Galium liratum N. A. Wakef.; Galium litorale Guss.; Galium lovcense Urum.; Galium lucidum All.; Galium macedonicum Krendl; Galium magellanicum Hook. f.; Galium magellense Ten.; Galium magnifolium (Dempster) Dempster; Galium mahadivense G. Singh; Galium malickyi Krendl.; Galium mandonii Britton; Galium maneauense P. Royen; Galium marchandii Roem. & Schult.; Galium margaceum Ehrend. & Schönb.-Tem.; Galium margaritaceum A. Kern.; Galium maritimum L.; Galium martirense Dempster & Stebbins; Galium masafueranum Skottsb.; Galium matthewsii A. Gray; Galium maximowiczii (Kom.) Pobed.; Galium mechudoense Dempster; Galium megacyttarion R. R. Mill; Galium megalanthum Boiss.; Schweizer Labkraut (Galium megalospermum All.); Galium megapotamicum Spreng.; Galium melanantherum Boiss.; Galium meliodorum (Beck) Fritsch; Galium membranaceum Ehrend.; Galium mexicanum Kunth; Galium microchiasma Gilli; Galium microlobum I. Thomps.; Galium microphyllum A. Gray; Galium migrans Ehrend. & McGill.; Galium minutissimum T. Shimizu; Galium minutulum Jord.; Galium mirum Rech. f.; Galium mite Boiss. & Hohen.; Galium moldavicum (Dobrocz.) Franco; Galium mollugo L.; Galium monachinii Boiss. & Heldr.; Galium monasterium Krendl; Galium monticolum Sond.; Galium montis-arerae Merxm. & Ehrend.; Galium moralesianum Ortega Oliv. & Devesa; Galium moranii Dempster; Galium morii Hayata; Galium mucroniferum Sond.; Galium muelleri (K. Schum.) Dempster; Galium multiflorum Kellogg; Galium munzii Hilend & J. T. Howell; Galium murale (L.) All.; Galium murbeckii Maire; Galium muricatum W. Wight; Galium x mutabile Besser (Galium mollugo x Galium verum); Galium nabelekii Ehrend. & Schönb.-Tem.; Galium nakaii Kudo; Galium nankotaizanum Ohwi; Galium x neglectum Le Gall ex Gren. & Godr. (Galium album x Galium arenarium); Galium nepalense Ehrend. & Schönb.-Tem.; Galium nevadense Boiss. & Reut.; Galium nigdeense Y1ld.; Galium nigricans Boiss.; Galium nigroramosum (Ehrend.) Dempster; Galium nolitangere Ball; Galium noricum Ehrend.; Galium normanii Dahl; Galium novoguineense Diels; Galium noxium (A. St.-Hil.) Dempster; Galium numidicum Pomel; Galium nupercreatum Popov; Galium nuttallii A. Gray; Galium obliquum Vill.; Galium obovatum Kunth; Galium obtusum Bigelow; Galium octonarium (Klokov) Pobed.; Galium odoratum (L.) Scop.; Galium oelandicum Ehrend.; Galium olgae Klokov; Galium olivetorum Le Houér; Galium olympicum Boiss.; Galium ophiolithicum Krendl; Galium oreganum Britton; Galium oreophilum Krendl; Galium oresbium Greenm.; Galium orizabense Hemsl.; Galium oshtenicum Ehrend. & Schanzer ex Mikheev; Galium ossirwaense K. Krause; Galium ostenianum (Standl.) Dempster; Galium ovalleanum Phil.; Galium pabulosum Sommier & Levier; Galium palaeoitalicum Ehrend.; Galium palustre L.; Galium pamiroalaicum Pobed.; Galium pamphylicum Boiss. & Heldr.; Galium paniculatum (Bunge) Pobed.; Galium papilliferum Ehrend. & Schönb.-Tem.; Galium papillosum Lapeyr.; Galium papuanum Wernham; Galium paradoxum Maxim.; Galium parishii Hilend & J. T. Howell; Galium parisiense L.; Galium parvulum Hub.-Mor. ex Ehrend. & Schönb.-Tem.; Galium paschale Forssk.; Galium pastorale Krendl; Galium patzkeanum G. H. Loos; Galium peloponnesiacum Ehrend. & Krendl; Galium penduliflorum Boiss.; Galium pendulum Greenm.; Galium penicillatum Boiss.; Galium pennellii Dempster; Galium peplidifolium Boiss.; Galium perralderi Coss.; Galium peruvianum Dempster & Ehrend.; Galium pestalozzae Boiss.; Galium petrae Oliv. ex Hart; Galium philippianum Dempster; Galium philippinense Merr.; Galium philistaeum Boiss.; Galium pilosum Aiton; Galium pisiferum Boiss.; Galium pisoderium Krendl; Galium platygalium (Maxim.) Pobed.; Galium plumosum Rusby; Galium poiretianum Ball; Galium pojarkovae Pobed.; Galium polyacanthum (Baker) Puff; Galium polyanthum I. Thomps.; Galium x pomeranicum Retz. (Galium album x Galium verum); Galium porrigens Dempster; Galium praemontanum Mardal.; Galium praetermissum Greenm.; Galium x pralognense Beauverd (Galium pumilum x Galium verum); Galium prattii Cufod.; Galium pringlei Greenm.; Galium problematicum (Ehrend.) Ehrend. & Schönb.-Tem.; Galium procurrens Ehrend.; Galium productum Lowe; Galium x prolazense Nyár. (Galium album x Galium flavescens); Galium proliferum A. Gray; Galium propinquum A. Cunn.; Galium pruinosum Boiss.; Galium pseudoaristatum Schur; Galium x pseudoboreale Klokov (Galium boreale x Galium rubioides); Galium pseudocapitatum Hub.-Mor. ex Ehrend. & Schönb.-Tem.; Galium pseudohelveticum Ehrend.; Galium pseudokurdicum (Ehrend.) Schönb.-Tem.; Galium pseudorivale Tzvelev; Galium pseudotriflorum Dempster & Ehrend.; Galium psilocladum Ehrend.; Galium pterocarpum Ehrend.; Galium pulvinatum Boiss.; Galium pumilio Standl.; Galium pumilum Murray; Galium pusillosetosum H. Hara; Galium pusillum L.; Galium pyrenaicum Gouan; Galium qaradaghense Schönb.-Tem.; Galium x querceticola Wol. (Galium abaujense subsp. polonicum x Galium intermedium); Galium quichense Dempster; Galium radulifolium Ehrend. & Schönb.-Tem.; Galium ramboi Dempster; Galium rebae R. R. Mill; Galium reiseri Halácsy; Galium x retzii Bouchard (Galium papillosum x Galium verum); Galium rhodopeum Velen.; Galium richardianum (Gillies ex Hook. & Am.) Endl. ex Walp.; Galium rigidifolium Krendl; Galium rivale (Sibth. & Sm.) Griseb.; Galium roddii Ehrend. & McGill.; Galium rosellum (Boiss.) Boiss. & Reut.; Galium rotundifolium L.; Galium rourkei Puff; Galium rubidiflorum Dempster; Galium rubioides L.; Galium rubrum L.; Galium runcinatum Ehrend. & Schönb.-Tem.; Galium rupifragum Ehrend.; Galium ruwenzoriense (Cortesi) Ehrend.; Galium rzedowskii Dempster; Galium sacrorum Krendl; Galium saipalense Ehrend. & Schönb.-Tem.; Galium salsugineum Krylov & Serg.; Galium salwinense Hand.-Mazz.; Galium samium Krendl; Galium samuelssonii Ehrend.; Galium saturejifolium Trevir.; Galium saurense Litv.; Galium saxatile L., Syn.: Galium harcynicum Weigel, Galium pawlowskii Kucowa, Galium pumilum subsp. saxatile (L.) Dostál; Galium saxosum (Chaix) Breistr.; Galium scabrelloides Puff; Galium scabrellum K. Schum.; Galium scabrifolium (Boiss.) Hausskn.; Galium scabrum L.; Galium schlumbergeri Boiss.; Galium x schmidelyi Chenevard & W. Wolf (Galium mollugo x Galium rubrum); Galium schmidii Arrigoni; Galium x schneebergense Ronniger (Galium anisophyllon x Galium meliodorum); Galium schoenbeck-temesyae Ehrend.; Galium scioanum Chiov.; Galium scopulorum Schönb.-Tem.; Galium seatonii Greenm.; Galium sellowianum (Cham.) Walp.; Galium semiamictum Klokov; Galium serpenticum Dempster; Galium serpylloides Royle ex Hook. f.; Galium setaceum Lam.; Galium setuliferum Ehrend. & Schönb.-Tem.; Galium shanense R. Bhattacharjee; Galium shepardii Post; Galium shepherdii Jung-Mend.; Galium sichuanense Ehrend.; Galium sidamense Chiov. ex Chiarugi; Galium sieheanum Ehrend.; Galium simense Fresen.; Galium similii Pavlov; Galium sinaicum (Delile ex Decne.) Boiss.; Galium smithreitzii Dempster; Galium sojakii Ehrend. & Schönb.-Tem.; Galium songaricum Schrenk; Galium sorgerae Ehrend. & Schönb.-Tem.; Galium sparsiflorum W. Wight; Galium spathulatum I. Thomps.; Galium speciosum Krendl; Galium sphagnophilum (Greenm.) Dempster; Galium spurium L.; Galium stellatum Kellogg; Galium stenophyllum Baker; Galium stepparum Ehrend. & Schönb.-Tem.; Galium sterneri Ehrend.; Galium subfalcatum Nazim. & Ehrend.; Galium subnemorale Klokov & Zaver.; Galium subtrifidum Reinw. ex Blume; Galium subtrinervium Ehrend. & Schönb.-Tem.; Galium subuliferum Sommier & Levier; Galium subvelutinum (DC.) K. Koch; Galium subvillosum Sond.; Galium sudeticum Tausch; Galium suecicum (Sterner) Ehrend.; Galium suffruticosum Hook. & Am. (Rubia margaritifera Reiche); Galium sungpanense Cufod.; Galium surinamense Dempster; Galium sylvaticum L.; Galium taiwanense Masam.; Galium takasagomontanum Masam.; Galium talaveranum Ortega Oliv. & Devesa; Galium tanganyikense Ehrend. & Verdc.; Galium tarokoense Hayata; Galium taygeteum Krendl; Galium tendae Rchb. f.; Galium tenuissimum M. Bieb.; Galium terraereginae Ehrend. & McGill.; Galium tetraphyllum Nazim. & Ehrend.; Galium texense A. Gray; Galium thasium Stoj. & Kitanov; Galium thiebautii Ehrend.; Galium thracicum Krendl; Galium thunbergianum Eckl. & Zeyh.; Galium thymifolium Boiss. & Heldr.; Galium tianschanicum Popov; Galium timeroyi Jord.; Galium tinctorium L.; Galium tmoleum Boiss.; Galium tokyoense Makino; Galium tolosianum Boiss. & Kotschy; Galium tomentosum Thunb.; Galium tortumense Ehrend. & Schönb.-Tem.; Galium transcarpaticum Stojko & Tasenk.; Galium trichocarpum DC.; Galium tricornutum Dandy; Galium trifidum L.; Galium trifloriforme Kom.; Galium triflorum Michx.; Galium trilobum Colenso; Galium trinioides Pomel; Galium trojanum Ehrend.; Galium truniacum (Ronniger); Galium tubiflorum Ehrend.; Galium tuncelianum Y1ld.; Galium tunetanum Lam.; Galium turgaicum Knjaz.; Galium turkestanicum Pobed.; Galium tyraicum Klokov; Galium uliginosum L.; Galium uncinulatum DC.; Galium undulatum Puff; Galium uniflorum Michx.; Galium uruguayense Bacigalupo; Galium valantioides M. Bieb.; Galium valdepilosum Heinr. Braun; Galium valentinum Lange; Galium vartanii Grossh.; Galium vassilczenkoi Pobed.; Galium velenovskyi Ancev; Galium verrucosum Huds.; Galium verticillatum Danthoine ex Lam.; Galium verum L.; Galium verum subsp. asiaticum (Nakai) T. Yamaz.; Galium verum subsp. glabrescens Ehrend.; Galium verum L. subsp. verum; Galium verum subsp. wirtgenii (F. W. Schultz) Oborny (Syn. Galium wirtgenii F. W. Schultz); Galium x viciosorum Sennen & Pau (Galium maritimum x Galium verum); Galium vile (Cham. & Schltdl.) Dempster; Galium violaceum Krendl; Galium virgatum Nutt.; Galium viridiflorum Boiss. & Reut.; Galium viscosum Vahl; Galium volcanense Dempster; Galium volhynicum Pobed.; Galium watsonii (A. Gray) A. Heller; Galium weberbaueri K. Krause; Galium wendelboi Ehrend. & Schönb.-Tem.; Galium werdermannii Standl.; Galium wigginsii Dempster; Galium wrightii A. Gray; Galium xeroticum (Klokov) Pobed.; Galium xylorrhizum Boiss. & A. Huet; Galium yunnanense H. Hara & C. Y. Wu; Galium zabense Ehrend.; Rubia agostinhoi Dans. & P. Silva; Rubia aitchisonii Deb & Malick; Rubia alaica Pachom.; Rubia alata Wall.; Rubia albicaulis Boiss.; Rubia angustisissima Wall. ex G. Don; Rubia argyi (H. Lév. & Vaniot) Hara ex Lauener, Syn.; Rubia akane Nakai, Rubia chekiangensis Deb, Rubia nankotaizana (Masam); Rubia atropurpurea Decne.; Rubia austrozhejiangensis Z. P. Lei, Y. Y. Zhou & R. W. Wang; Rubia balearica (Willk.) Porta; Rubia balearica (Willk.) Porta subsp. balearica; Rubia balearica subsp. caespitosa (Font Quer & Marcos) Rosselló, L. Sáez & Mus (Rubia angustifolia var. caespitosa Font Quer & Marcos, Rubia angustifolia subsp. caespitosa (Font Quer & Marcos) Rosselló, Rubia caespitosa (Font Quer & Marcos) Rosselló); Rubia caramanica Bornm.; Rubia charifolia Wall. ex G. Don.; Rubia chinensis Regel & Maack; Rubia chinensis f. chinensis (Rubia chinensis f. mitis (Miq.) Kitag.); Rubia chinensis f. glabrescens (Nakai) Kitag.; Rubia chitralensis Ehrend.; Rubia clematidifolia Blume ex Decne.; Rubia cordifolia L.; Rubia cordifolia subsp. conotricha (Gand.) Verdc.; Rubia cordifolia subsp. cordifolia; Rubia crassipes Collett & Hemsl.; Rubia cretacea Pojark.; Rubia danaensis Danin; Rubia davisiana Ehrend.; Rubia deserticola Pojark.; Rubia discolor Turcz.; Rubia dolichophylla Schrenk; Rubia edgeworthii Hook. f.; Rubia falciformis H. S. Lo; Rubia filiformis F. C. How ex H. S. Lo; Rubia florida Boiss; Rubia garrettii Craib; Rubia gedrosiaca Bornm.; Rubia haematantha Airy Shaw; Rubia hexaphylla (Makino) Makino; Rubia hispidicaulis D. G. Long; Rubia infundibularis Hemsl. & Lace; Rubia jesoensis (Miq.) Miyabe & Kudo; Rubia komarovii Pojark; Rubia krascheninnikovii Pojark; Rubia laevissima Tsckern.; Rubia latipetala H. S. Lo; Rubia laurae (Holmboe) Airy Shaw; Rubia laxiflora Gontsch.; Rubia linii J. M. Chao; Rubia magna P. G. Xiao; Rubia mandersii Collett & Hemsl.; Rubia manjith Roxb. ex Fleming; Rubia maymanensis Ehrend. & Schönb.-Tem; Rubia membranacea Diels; Rubia oncotricha Hand.-Mazz.; Rubia oppositifolia Griff.; Rubia ovatifolia Z. Ying Zhang ex Q. Lin; Rubia pallida Diels; Rubia pauciflora Boiss.; Rubia pavlovii Bajtenov & Myrz.; Rubia peregrina L.; Rubia petiolaris DC.; Rubia philippinensis Elmer; Rubia pianmaensis R. Li & H. Li; Rubia podantha Diels; Rubia polyphlebia H. S. Lo; Rubia pseudogalium Ehrend.; Rubia pterygocaulis H. S. Lo; Rubia rechingeri Ehrend.; Rubia rezniczenkoana Litv.; Rubia rigidifolia Pojark.; Rubia rotundifolia Banks & Sol.; Rubia salicifolia H. S. Lo; Rubia schugnanica B. Fedtsch. ex Pojark.; Rubia schumanniana E. Pritz.; Rubia siamensis Craib; Rubia sikkimensis Kurz; Rubia sylvatica (Maxim.) Nakai; Rubia tatarica (Trevir.) F. Schmidt; Rubia tenuifolia d'Urv.; Rubia tenuifolia subsp. brachypoda (Boiss.) Ehrend. & Schönb.-Tem.; Rubia tenuifolia subsp. doniettii (Griseb.) Ehrend. & Schönb.-Tem.; Rubia tenuifolia subsp. Tenuifolia; Rubia tenuissima fined. (Syn.: Rubia tenuis H. S. Lonom. illeg.); Rubia thunbergii DC.; Rubia tibetica Hook. f.; Rubia tinctorum L.; Rubia transcaucasica Grossh.; Rubia trichocarpa H. S. Lo; Rubia truppeliana Loes.; Rubia wallichiana Decne.; and Rubia yunnanensis Diels; preferably a plant selected from Galium aparine, Galium verum and Rubia cardifolia L.; (ii) from a fungus of a fungal genus selected from the group consisting of: Alternaria genus; Aspergillus genus, preferably Aspergillus chevalieri, Aspergillus glaucus and Aspergillus fumigatus; Boletus genus, preferably comprising Boletol and Carminic acid; Cortinarius genus; Curvularia genus; Eurotium genus; Fusarium genus; Haloresellinia genus; Helminthosporium genus, preferably H. cynodontis, H. catenarium and H. triticivulgaris; Microshaeropsis genus; Monodictys genus; Nigrospora genus; Paecilomyces genus; Penicillium genus, preferably P. cyclopium, P. citreo-roseum, P. carmine-violaceum, P. roseo-purpureum and P. cyclopium; Phomopsis; Preussia genus, preferably Pressuia multispora (Saito et Minoura) Cain; Valsaria genus, preferably Valsaria rubricosa, preferably comprising Papulosin, valsarin; Talaromyces genus, preferably Talaromyces avellaneus (Thom et Turreson) C. R. Benjamin; or (iii) from a fungus of a Lichen genus, preferably a Lichen genus selected from the group consisting of Xanthoria genus, preferably Xanthoria parietina; Lecidella genus, preferably Lecidella asema; Lasallia genus, preferably Lasallia papulose var. rubiginosa; Trypethelium genus, preferably Trypethelium cruentum (Pyrenula cruenta).
27. The method according to claim 20, wherein the anthraquinone or anthraquinone derivative is an anthraquinone or anthraquinone derivative according to formula (IIIa), wherein R.sup.1, R.sup.3, R.sup.6, R.sup.7, and R.sup.8 are each independently selected from the group consisting of: (i) —OMe and —OEt, or —O(C═O)Me; (ii) —COOH, —COOMe or COOEt; (iii) substituted or non-substituted —CHO, methyl, ethyl or propyl; (iv) (C.sub.3)carbocycle, (C.sub.5-6)carbocycle, aromatic (C.sub.6)carbocycle, a non-substituted phenyl or a phenyl that is substituted by a substituent selected from the group consisting of Cl, F, Br, substituted or non-substituted methyl, —(CF.sub.3), ethyl, propyl and cyclopropyl; (v) substituted or non-substituted heterobicycle having 2 oxygen atoms, or substituted or non-substituted benzodioxolyl connected via position (5) or (6) of the benzodioxolyl; and (vi) a mono-, di- or trisaccharide.
28. The method according to claim 20, wherein the anthraquinone or anthraquinone derivative is an anthraquinone or anthraquinone derivative according to Formula (IIIa), ##STR00027## wherein: R.sup.6 and R.sup.7 are hydrogen; R.sup.8 is a linear or branched, substituted or non-substituted (C.sub.1-10)alkyl, (C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl; R.sup.1 is OH or —O(C.sub.1-10)alkyl, or —O(C═O)(C.sub.1-10)alkyl; and R.sup.3 is OH, a linear or branched, substituted or non-substituted (C.sub.1-10)alkyl, (C.sub.2-10)alkenyl, (C.sub.2-10)alkynyl, —O(C.sub.1-10)alkyl, —O(C.sub.3-10)cycloalkyl, —O(C═O)(C.sub.1-10)alkyl, —O(C═O)(C.sub.3-10)cycloalkyl, —COOH, COOMe, COOEt, or C(C═O)NH.sub.2.
29. The method according to claim 28, wherein: R.sup.8 is substituted or non-substituted methyl, ethyl or propyl; R.sup.1 is —OMe, —OEt, —O(C═O)Me or OH; and R.sup.3 is substituted or non-substituted methyl, ethyl, propyl, —OMe, —OEt, —O-cyclopropyl, —O(C═O)Me, or —O(C═O)-cyclopropyl.
30. The method according to claim 20, wherein the anthraquinone or anthraquinone derivative is an anthraquinone or anthraquinone derivative according to Formula (IIId), ##STR00028## wherein: R.sup.1 to R.sup.8 are each independently selected from the group consisting of: (i) H, F, Cl, Br, —CN, —OH, —OSO.sub.3H and —SO.sub.3H; (ii) —OMe, —OEt, —O-cyclopropyl, —O(C═O)cyclopropyl, —O(C═O)(C.sub.1-3)alkyl and —O(C═O)Me; (iii) —COOH, —COOMe and COOEt; (iv) linear or branched, substituted or non-substituted (C.sub.2-10)alkyl ether, (C.sub.3-10)alkenyl ether, (C.sub.3-10)alkynyl ether or (C.sub.4-10)carbocyclic ether, wherein the ether is bonded to formula (Ind) via its carbon atom; (v) linear or branched, substituted or non-substituted (C.sub.1-10)alkyl; (vi) substituted or non-substituted carbocycle selected from the group consisting of (C.sub.3)carbocycle, (C.sub.5-6)carbocycle, and aromatic (C.sub.6)carbocycle; and (vii) substituted or non-substituted heterobicycle having 2 oxygen atoms, or substituted or non-substituted benzodioxolyl connected via position (5) or (6) of the benzodioxolyl; or R.sup.2 and R.sup.3 together form a ring selected from the group consisting of (i) substituted or non-substituted (C.sub.3)carbocycle, (C.sub.5-6)carbocycle and aromatic (C.sub.6)carbocycle; and (ii) substituted or non-substituted heterobicycle having 2 oxygen atoms.
31. The method according to claim 28, wherein: R.sup.1 and R.sup.2 are —OH; and R.sup.3 to R.sup.8 are each independently selected from the group consisting of: (i) substituted or non-substituted —CHO, methyl, ethyl or propyl; (ii) non-substituted phenyl or a phenyl that is substituted by a substituent selected from the group consisting of Cl, F, Br, substituted or non-substituted methyl, —(CF.sub.3), ethyl, propyl and cyclopropyl; and (iii) non-substituted phenyl or a phenyl that is substituted by a substituent selected from the group consisting of Cl, F, Br, substituted or non-substituted methyl, —(CF.sub.3), ethyl, propyl and cyclopropyl.
32. The method according to claim 20, wherein the anthraquinone or anthraquinone derivative is an anthraquinone or anthraquinone derivative according to Formula (IIId), ##STR00029## wherein R.sup.1 to R.sup.8 are each independently selected from the group consisting of: (i) H, F, Cl, —CN, —OH, and —OSO.sub.3H; (ii) —O(C.sub.1-10)alkyl and —O(C.sub.2-10)alkenyl; (iii) —O(C═O)(C.sub.1-10)alkyl and —O(C═O)(C.sub.2-10)alkenyl (iv) —COOH, —COONH.sub.2, —COOMe or —COOEt; (v) linear or branched, substituted or non-substituted (C.sub.2-10)alkyl ether wherein the ether is bonded to formula (IIId) via its carbon atom; (vi) linear or branched, substituted or non-substituted (C.sub.1-10)alkyl or (C.sub.2-10)alkenyl; (vii) substituted or non-substituted carbocycle (C.sub.3-6)carbocycle; and (viii) substituted or non-substituted (C.sub.3-6)heterocycle or (C.sub.7-10)carbo- or hetero-bicycle having 1 to 3 heteroatoms each independently selected from N, O and S.
33. The method according to claim 32, wherein R.sup.1 to R.sup.8 are each independently selected from the group consisting of: (i) —OMe, —OEt, —O-propyl and —O-cyclopropyl; (ii) —O(C═O)propyl, —O(C═O)cyclopropyl, —O(C═O)Me and —O(C═O)Et; (iii) an ether selected from the group consisting of ##STR00030## (iv) ##STR00031## (v) a substituted or non-substituted carbocycle selected from the group consisting of phenyl, benzenediol, cyclohexyl, cyclopentyl, and cyclopenta-1,3-dienyl; and (vi) substituted or non-substituted benzodioxolyl connected via position (5) or (6) of the benzodioxolyl.
34. The method according to claim 32, wherein R.sup.2 and R.sup.3 together form a ring selected from the group consisting of: (i) substituted or non-substituted (C.sub.3-10)carbocycle; and (ii) substituted or non-substituted (C.sub.3-6)heterocycle or (C.sub.7-10)carbo- or hetero-bicycle having 1 to 3 heteroatoms each independently selected from N, O and S.
35. The method according to claim 32, wherein R.sup.2 and R.sup.3 together form a ring selected from the group consisting of substituted or non-substituted heterobicycle having 2 oxygen atoms, ##STR00032##
36. The method according to claim 32, wherein R.sup.1 and R.sup.2 are selected from the group consisting of: (i) F, Cl, —CN and —OH; (ii) O(C.sub.1-10)alkyl and —O(C.sub.2-10)alkenyl; and (iii) —O(C═O)(C.sub.1-10)alkyl and —O(C═O)(C.sub.2-10)alkenyl, —O(C═O)propyl, and —O(C═O)cyclopropyl; R.sup.3 is H, F, —COOH, —COONH.sub.2, —COOMe or —COOEt; R.sup.4 is selected from the group consisting of (i) H, F, Cl and —OH; (ii) O(C.sub.1-10)alkyl and —O(C.sub.2-10)alkenyl and —O-cyclopropyl; and (iii) O(C═O)(C.sub.1-10)alkyl and —O(C═O)(C.sub.2-10)alkenyl —O(C═O)propyl, and —O(C═O)cyclopropyl; and R.sup.5 to R.sup.8 are H or F.
37. The method according to claim 20, wherein the anthraquinone or anthraquinone derivative is selected from the group consisting of: 1,2-dihydroxyanthracene-9,10-dione (Alizarin); 1,3,4-trihydroxy-9,10-dioxo-anthracene-2-carboxylic acid (Pseudopurpurin); 1,2,4-trihydroxyanthracene-9,10-dione (Purpurin); 1,3-dihydroxy-2-methyl-anthracene-9,10-dione (Rubiadin); 1,3,-dihydroxy-2(hydroxymethyl)anthracene-9,10-dione (Lucidin); 2-methylanthracene-9,10-dione (Tectochinone); 2-(hydroxymethyl)anthracene-9,10-dione; 2-methoxyanthracene-9,10-dione; 2-hydroxyanthracene-9,10-dione; 1-hydroxyanthracene-9,10-dione; 1-hydroxy-2-methyl-anthracene-9,10-dione; 1-hydroxy-2-(hydroxymethyl)anthracene-9,10-dione; ethyl 1-hydroxy-9,10-dioxo-anthracene-2-carboxylate; 1-methoxy-2-methyl-anthracene-9,10-dione; 1-hydroxy-2-methoxy-anthracene-9,10-dione; 2-hydroxy-1-methoxy-anthracene-9,10-dione; 1,2,-dimethoxyanthracene-9,10-dione; 1,3-dihydroxy-9,10-dioxo-anthracene-2-carbaldehyde; 1,3-dihydroxy-9,10-dioxo-anthracene-2-carboxylic acid; methyl-1,3-dihydroxy-9,10-dioxo-anthracene-2-carboxylate; 2-(ethoxymethyl)-1,3,-dihydroxy-anthracene-9,10-dione; 1,3-dihydroxy-2-(methoxymethyl)anthracene-9,10-dione; 2-(hydroxymethyl)-1,3-dimethoxy-anthracene-9,10-dione; 1,3-dihydroxy-9,10-dioxo-anthracene-2-carboxylic acid; 1,3-dimethoxy-9,10-dioxo-anthracene-2-carboxylic acid; 1,2,3-trihydroxyanthracene-9,10-dione; 1,3-dihydroxyanthracene-9,10-dione; 1,3-dihydroxy-2-phenyl-anthracene-9,10-dione; 2-benzyl-1,3-dihydroxy-anthracene-9,10-dione; 1,3-dihydroxy-2-methoxy-anthracene-9,10-dione; 1,2-dihydroxy-3-methoxy-anthracene-9,10-dione; 1-hydroxy-2,3-dimethoxy-anthracene-9,10-dione; 1-hydroxy-3-methoxy-9,10-dioxo-anthracene-2-carboxylic acid; 3-hydroxy-1-methoxy-2-(methoxymethyl)anthracene-9,10-dione; 1,4-dihydroxyanthracene-9,10-dione (Quinizarin); 1,4-dihydroxy-2-(hydroxymethyl)anthracene-9,1-dione; ethyl-1,4-dihydroxy-9,10-dioxo-anthracene-2-carboxylate; 2-(ethoxymethyl)-1,4-dihydroxy-anthracene-9,10-dione (Christofin); 1,4-dihydroxy-2-methyl-anthracene-9,10-dione; 1-hydroxy-3-methoxy-anthracene-9,10-dione; 1,3-dimethoxyanthracene-9,10-dione; methyl-4-hydroxy-9,10-dioxo-anthracene-2-carboxylate; 1,4-dihydroxy-5-methoxy-2-methyl-anthracene-9,10-dione; 1,4-dihydroxy-8-methoxy-2-methyl-anthracene-9,10-dione; 1,4-dihydroxy-6-methyl-anthracene-9,10-dione; 1,5-dihydroxy-2-methyl-anthracene-9,10-dione; 1,8-dihydroxy-3-methoxy-6-methyl-anthracene-9,10-dione (Physcion, Parietin); 1,3,6-trihydroxy-2-methyl-anthracene-9,10-dione; 1,8-dihydroxy-3-methoxy-6-methyl-anthracene-9,10-dione; 3,6-dihydroxy-1-methoxy-2-methyl-anthracene-9,10-dione; 2-hydroxy-7-methyl-anthracene-9,10-dione; 4-hydroxy-9,10-dioxo-anthracene-9,10-dione; 1,6-dihydroxy-2-methyl-anthracene-9,10-dione; 1,3,8-trihydroxy-6-(hydroxymethyl)anthracene-9,10-dione (Citreorosein); 1,8-dihydroxy-3-(hydroxymethyl)-6-methoxy-anthracene-9,10-dione (Telochistin); 1,8-dihydroxy-3,6-dimethoxy-anthracene-9,10-dione (Fallacinol); 1,3,6,8-tetrahydroxy-2-[E-styryl]anthracene-9,10-dione (Averythrin); 1,6,8-trihydroxy-3-methyl-9,10-dioxo-anthracene-2-carboxylic acid (Endocrocin); 1,4,5-trihydroxy-7-methoxy-2-methyl-anthracene-9,10-dione; 1,4,5,7-tetrahydroxy-2-(hydroxymethyl)anthracene-9,10-dione (Tritisporin); 1,5,8-trihydroxy-3-methyl-anthracene-9,10-dione (Helminthosporin); 1,4,5,8-tetrahydroxy-2-methyl-anthracene-9,10-dione (Cynodontin); 7-alpha-D-Glucopyranosyl-9,10-dihydro-3,5,6,8-tetrahydroxy-1-methyl-9,10-dioxoanthracenecarboxylic acid (Carminic acid); 1,5,-dihydroxy-8-methoxy-3-methyl-anthracene-9,10-dione (Questin); 4,5,7-trihydroxy-9,10-dioxo-anthracene-2-carboxylic acid (Emodic acid); 1,6-dihydroxy-3-(hydroxymethyl)-8-methoxy-anthracene-9,10-dione (Questinol); 1,3-dihydroxy-6-(hydroxymethyl)-8-methoxy-anthracene-9,10-dione (Carviolin); 1,3,8-trihydroxy-6-(hydroxymethyl)anthracene-9,10-dione (Citreorosein); 2,8-dihydroxy-1-methoxy-3-methyl-anthracene-9,10-dione; 3-acetyl-1,2,4,5,7-pentahydroxy-anthracene-9,10-dione; 4,5-dihydroxy-9,10-dioxo-anthracene-2-carboxylic acid (Rhein); 1,4,5,7-tetrahydroxy-2-methyl-anthracene-9,10-dione (Catenarin); 1,8-dihydroxy-3-(hydroxymethyl)anthracene-9,10-dione (Aloe-emodin); 1,8-dihydroxy-3-methyl-anthracene-9,10-dione (Chrysophanol); Rhein-8-glucoside; 1,3,8-trihydroxy-6-methyl-anthracene-9,10-dione (Alatinone); 4,5-diacetoxy-7-hydroxy-9,10-dioxo-anthracene-2-carboxylic acid (Diacerhein); 1,3,5,8-tetrahydroxy-6-methyl-anthracene-9,10-dione; 1,4-dihydroxy-6,7-dimethoxy-3-methyl-9,10-dioxo-anthracene-2-carboxylic acid; 1,3-dihydroxy-6,8-dimethoxy-anthracene-9,10-dione; 1,3,5,8-tetrahydroxy-2-methyl-anthracene-9,10-dione; 1,3,8-trihydroxy-2-methyl-1,2-dihydroanthracene-9,10-dione; 1-methoxy-anthracene-9,10-dione; 1,8-dihydroxy-6-methoxy-2-methyl-anthracene-9,10-dione; 1,8-dihydroxy-3-methoxy-6-methyl-anthracene-9,10-dione; 2,3,4,8-tetrahydroxy-6-methoxy-3-methyl-2,4-dihydro-1H-anthracene-9,10-dione; 1,3,6,8-tetrahydroxyanthracene-9,10-dione; 2,3,5-trihydroxy-7-methyl-1,2,3,4-tetrahydroanthracene-9,10-dione; 1,3-dihydroxy-8-methoxy-6-methyl-anthracene-9,10-dione; 1,3,7-trihydroxy-6-(2-hydroxypropyl)anthracene-9,10-dione; 1,3,6,8-tetrahydroxy-2-(1-hydroxyethyl)anthracene-9,10-dione; 2-chloro-1,6-dihydroxy-8-methoxy-3-methyl-anthracene-9,10-dione; 1,3,6,8-tetrahydroxy-2-(1-methoxyethyl)anthracene-9,10-dione; 1,3,8-trihydroxy-9,10-dioxo-anthracene-2-carbaldehyde; 2,16,18-trihydroxy-7,9-dioxapentacyclo[10.8.0.03,10.04,8.014,19]icosa-1(12),2,10,14(19),15,17-hexaene-13,20-dione; 2,16,18-trihydroxy-7,9-dioxapenta-cyclo[10.8.0.03,10.04,8.014,19]icosa-1(12),2,5,10,14(19),15,17-heptaene-13,20-dione; 4-hydroxy-5-methoxy-9,10-dioxo-anthracene-2-carbaldehyde; 6,8-dimethoxy-1-methyl-2-(3-oxobutyl)anthracene-9,10-dione; 2-[(E)-hex-1-enyl]-1,3,6,8-tetrahydroxy-anthracene-9,10-dione; 3,7-dihydroxy-9-methoxy-17-methyl-16,21-dioxapentacyclo[15.3.1.02,15.04,-13.06,11]henicosa-2,4(13),6(11),7,9,14-hexaene-5,12-dione; 1,3,6,8-tetrahydroxy-2-(1-methoxyhexyl)anthracene-9,10-dione; 1,3,6,8-tetrahydroxy-2-(1-hydroxyhexyl)anthracene-9,10-dione; 2-chloro-1,3,6,8-tetrahydroxy-7-(1-hydroxyhexyl)anthracene-9,10-dione; 2-(1-butoxyhexyl)-7-chloro-1,3,6,8-tetrahydroxy-anthracene-9,10-dione; 11-hydroxy-7-methyl-9,12-dioxo-4-oxa-1,8-diazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-13-carboxylic acid; 11-hydroxy-7,13-dimethyl-4-oxa-1,8-diazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-9,12-dione; 11-hydroxy-7-methyl-9,12-dioxo-4-oxa-1,8-diazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-13-carboxylic acid; 1,3-dihydroxy-2-phenyl-anthracene-9,10-dione; 2-(3,4-dihydroxyphenyl)-1,3-dihydroxy-anthracene-9,10-dione; 2-(1,3-benzodioxol-5-yl)-1,3-dihydroxy-anthracene-9,10-dione; 1,2,3,4,5,6,7,8-octafluoroanthracene-9,10-dione; 1,2-difluoroanthracene-9,10-dione; 1,2-dihydroxy-3,4,5,6,7,8-hexafluoro-anthracene-9,10-dione; 1,3,4,5,6,7,8-heptafluoro-9,10-dioxo-anthracene-2-carboxylic acid; 1,3,4-trifluoro-9,10-dioxo-anthracene-2-carboxylic acid; 1,3,4-trihydroxy-5,6,7,8-tetrafluoro-9,10-dioxo-anthracene-2-carboxylic acid; 1-hydroxy-3-methylanthraquinone; 1,3,6,8-Tetrahydroxyanthraquinone; Coniothranthraquinone 1 ((2S,3R)-2,3,5-trihydroxy-7-methyl-1,2,3,4-tetrahydroanthraquinone); Macrosporin (1,7-dihydroxy-3-methoxy-6-methylanthraquinone); Austrocortinin (1,4-dihydroxy-2-methoxy-7-methylanthraquinone); 1-Methylemodin (1,3-dihydroxy-8-methoxy-6-methylanthraquinone); Macrospin (1,6-dihydroxy-3-methoxy-7-methylanthraquinone); Monodictyquinone (1,8-dihydroxy-2-methoxy-6-methylanthraquinone); Lunatin (1,3,8-trihydroxy-6-methoxyanthraquinone); 2,8-dihydroxy-1,3-dimethoxy-6-methyl anthraquinone; Erythroglaucin (1,4,5-trihydroxy-7-methoxy-2-methylanthraquinone); Rubocristin (1,4,7-trihydroxy-5-methoxy-2-methylanthraquinone); 6-O-methylalaternin (1,2,8-trihydroxy-6-methoxy-3-methylanthraquinone); 1,4,6-Trihydroxy-2-methoxy-7-methyl-anthraquinone; 7-Chloro-emodin; Xylanthraquinone; Isorhodoptilometrin ((R)-1,3,8-trihydroxy-6-(2-hydroxypropyl)anthraquinone); 1,3,6,8-Tetrahydroxy-2-(1-hydroxyethyl) anthraquinone; 1-O-Methyl-7-chloroemodin (2-chloro-1,6-dihydroxy-8-methoxy-3-methylanthraquinone); 7-Chlorocitreorosein; Austrocortirubin (1,4-dihydroxy-2-methoxy-7-methylanthraquinone); Fragilin (2-chloro-1,8-dihydroxy-3-methoxy-6-methyl-anthraquinone); 5-Acetyl-2-methoxy-1,4,6-trihydroxyanthraquinone; Isorhodoptilometrin-1-methylether (1,3-dihydroxy-6-2-hydroxypropyl-8-methoxyanthraquinone); 1,3,6,8-Tetrahydroxy-2-(1-methoxyethyl)anthraquinone; Versicolorin C ((4,6,8-trihydroxy-3,3a-dihydroanthra[2,3-b]furo[3,2-d]furan-5,10(2H,12aH)-dione); 1,2,3,6,8-Pentahydroxy-7-(1-methoxyethyl)anthraquinone; Emodin-3-O-Sulfate ((4,5-dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracene-2-yl hydrogen sulfate); 8-O-MethylversicolorinB ((4,8-dihydroxy-6-methoxy-3,3a-dihydroanthra[2,3-b]furo[3,2-d]furan-5,10(2H,12aH)-dione); 6,8-Dimethoxy-1-methyl-2-(3-oxobutyl)anthraquinone; 8-O-Methylversicolorin A (4,8-dihydroxy-6-methoxyanthra[2,3-b]furo[3,2-d]furan-5,10(3aH,12aH)-dione); Averythrin ((E)-2-(hex-1-en-1-yl)-1,3,6,8-tetrahydroxyanthraquinone); Skyrin (2,2′,4,4′,5,5′-hexahydroxy-7,7′-dimethyl-[1,1′-bianthracene]-9,9′,10,10′-tetraone); Macrosporin-7-O-sulfate (Sodium 8-hydroxy-6-methoxy-3-methyl-9,10-dioxo-9,10-dihydroanthracene-2-yl sulfate); Citreorosein-3-O-sulfate (4,5-dihydroxy-7-(hydroxymethyl)-9,10-dioxo-9,10-dihydroanthracene-2-yl hydrogen sulfate); 6,8-di-O-methylversicolorinA (4-hydroxy-6,8-dimethoxyanthra[2,3-b]furo[3,2-d]furan-5,10(3aH,12aH)-dione); 8-O-Methylaverythrin ((E)-2-(hex-1-en-1-yl)-1,3,6-trihydroxy-8-methoxyanthraquinone); Aversin (4-hydroxy-6,8-dimethoxy-3,3a-dihydroanthra[2,3-b]furo[3,2-d]furan-5,10(2H,12aH)-dione); Aversin ((−)-isomer of (4-hydroxy-6,8-dimethoxy-3,3a-dihydroanthra[2,3-b]furo[3,2-d]furan-5,10(2H,12aH)-dione); Averantin ((S)-1,3,6,8-tetrahydroxy-2-(1-hydroxyhexyl)anthraquinone); 6-O-Methylaverufin (7,9-dihydroxy-11-methoxy-2-methyl-3,4,5,6-tetrahydro-2H-2,6-epoxyanthra[2,3-b]oxocine-8,13-dione); Nidurufin (5,7,9,11-tetrahydroxy-2-methyl-3,4,5,6-tetrahydro-2H-2,6-epoxyanthra[2,3-b]oxocine-8,13-dione); Averufin (7,9,11-trihydroxy-2-methyl-3,4,5,6-tetrahydro-2H-2,6-epoxyanthra[2,3-b]oxocine-8,13-dione); 1′-O-Methylaverantin (1,3,6,8-tetrahydroxy-2-(1-methoxyhexyl)anthraquinone); (2S)-2,3-Dihydroxy-propyl-1,6,8-trihydroxy-3-methyl-9,10-dioxoanthracene-2-carboxylate; 7-Chloroaverythrin ((E)-2-chloro-7-(hex-1-en-1-yl)-1,3,6,8-tetrahydroxyanthraquinone); 6,8-Di-O-methylversiconol (2-(1,4-dihydroxybutan-2-yl)-1,3-dihydroxy-6,8-dimethoxyanthraquinone); 6,8-Di-O-methylaverufin (7-hydroxy-9,11-dimetho-xy-2-methyl-3,4,5,6-tetra-hydro-2H-2,6-epoxyanthra[2,3-b]oxocine-8,13-dione); 6,8-Di-O-methylnidurufin (5,7-dihydroxy-9,11-dime-thoxy-2-methyl-3,4,5,6-tetrahydro-2H-2,6-epoxyanthra[2,3-b]oxocine-8,13-dione); 1,3-dihydroxy-6,8-dimethoxy-2-(6-methyltetra-hydro-2H-pyran-2-yl)anthracene-9,10-dione; 6,1′-O,O-Dimethylaverantin ((S)-1,3,8-trihydroxy-6-methoxy-2-(1-methoxyhexyl)anthraquinone); Variecolorquinone A ((S)-2,3-dihydroxypropyl 1,6-dihydroxy-8-methoxy-3-methyl-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate); 6,8-Di-O-methylaverantin ((S)-1,3-dihydroxy-2-(1-hydroxyhexyl)-6,8-dimetho-xyanthraquinone); 6-O-Methyl-7-chloroaverythrin ((E)-2-chloro-7-(hex-1-en-1-yl)-1,6,8-trihydroxy-3-methoxyanthraquinone); (1′S)-7-Chloroaverantin ((S)-2-chloro-1,3,6,8-tetrahydroxy-7-(1-hydroxyhexyl)anthraquinone); 6,1′-O,O-Dimethyl-7-chloroaverantin ((S)-2-chloro-1,6,8-trihydroxy-3-methoxy-7-(1-methoxyhexyl)anthraquinone); 6,8,1′-Tri-O-methyl-averantin (1,3-dihydroxy-6,8-dimethoxy-2-(1-methoxyhexyl)anthraquinone); 6-3-O-(Ribofuranosyl)questin (1,6-dihydroxy-6-O-(ribofuranosyl)-8-methoxy-3-methylanthraquinone); 1′-O-methyl-7-chloro averantin ((S)-2-chloro-1,3,6,8-tetrahydroxy-7-(1-methoxy-hexyl)anthraquinone); 6-O-methyl-7-chloro-averantin ((S)-2-chloro-1,6,8-trihydroxy-7-(1-hydroxyhexyl)-3-methoxyanthraquinone); Averantin-1′-butyl ether ((S)-2-(1-butoxyhexyl)-1,3,6,8-tetrahydroxy-anthraquinone); 7-Chloroaverantin-1′-butyl ether ((S)-2-(1-butoxyhexyl)-7-chloro-1,3,6,8-tetrahy-droxyanthraquinone); 6-O-Methyl-7-bromoaverantin ((S)-2-bromo-1,6,8-trihydroxy-7-(1-hydroxyhexyl)-3-methoxyanthraquinone); 6,1′-O,O-Dimethyl-7-bromoaverantin ((S)-2-bromo-1,6,8-trihydroxy-3-methoxy-7-(1-methoxyhexyl)anthraquinone); Macrosporin2-O-(6′-acetyl)-a-d-glucopyranoside ((2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6-((8-hydroxy-6-methoxy-3-methyl-9,10-dioxo-9,10-dihydroanthracene-2-yl)oxy)tetrahydro-2H-pyran-2-yl)methyl acetate); Penicillanthranin A ((1S,3R,4S)-1-(6-ethyl-1,3,8-trihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-yl)-6,8-dihy-droxy-3,4,5-trimethyliso-chroman-7-carboxylic acid); Penicillanthranin B ((1S,3R,4S)-6,8-dihydroxy-3,4,5-trimethyl-1-(1,3,8-trihydroxy-6-(hydroxy-methyl)-9,10-dioxo-9,10-dihydroanthracene-2-yl)isochroman-7-carboxylic acid); (trans)-R (cis)-Emodin-Physcion bianthrone (2,4,4′,5,5′-pentahydroxy-2′-methoxy-7,7′-dimethyl-[9,9′-bianthracene]-10,10′(9H,9′H)-dione); Alterporriol Q (1′,2,7′,8-tetrahydroxy-3′,6-dimethoxy-3,6′-dimethyl-[1,2′-bianthracene]-9,9′,10,10′-tetraone); Alterporriol R (2,4′,6′,8-tetrahydroxy-2′,6-dimethoxy-3,7′-dimethyl-[1,1′-bianthracene]-9,9′,10,10′-tetraone); Alterporriol V (2,2′,8,8′-tetrahydroxy-6,6′-dimethoxy-3,3′-dimethyl-[1,1′-bianthracene]-9,9′,10,10′-tetraone); Cytoskyrin A ((6R,14R,17S,18R,19R,20S)-1,7,9,15,17,20-hexahydroxy-3,11-dimethoxy-6,13a,5a,14-(epibutane[1,2,3,4]tetrayl)cycloocta[1,2-b:5,6-b′]dinaphtha-lene-5,8,13,16(6H,14H)-tetraone); Alterporriol K ((5S,8R)-4,4′,5,7′,8-penta-hydroxy-1,1′-dimethoxy-6′,8-dimethyl-5,6,7,8-tetrahydro-[2,2′-bianthracene]-9,9′,10,10′-tetraone); Alterporriol T ((6R,6′S,7R,7′R,8R)-1′,4,6,6′,7,7′,8-heptahydroxy-2,3′-dimethoxy-6′,7-dime-thyl-5,5′,6,6′,7,7′,8,8′-octahydro-[1,2′-bianthracene]-9,9′,10,10′-tetraone); Alterporriol L ((6S,7R,8R)-4,4′,6,7,7′,8-hexahydroxy-1,1′-dimethoxy-6′,7-dimethyl-5,6,7,8-tetrahydro-[2,2′-bianthracene]-9,9′,10,10′-tetraone); Alterporriol M ((6S,7S,8R)-4,4′,6,7,7′,8-hexahydroxy-1,1′-dimethoxy-6′,7-dimethyl-5,6,7,8-tetrahydro-[2,2′-bianthracene]-9,9′,10,10′-tetraone); Alterporriol P ((5′R,6′R,7′R)-1′,2,5′,6′,7′,8-hexahydroxy-3′,6-dimethoxy-3,6′-dimethyl-5′,6′,7′,8′,8′a,10′a-hexahydro-[1,2′-bianthracene]-9,9′,10,10′-tetraone); Alterporriol W ((1′R,6R,7R,8R)-2′,4,6,7,8,8′-hexahydroxy-2,6′-dimethoxy-3′,7-dimethyl-5,6,7,8-tetrahydro-[1,1′-bianthracene]-9,9′,10,10′-tetraone); Alterporriol U ((6R,6′S,7S,7′R)-1′,4,6,6′,7,7′-hexahydroxy-2,3′-di-methoxy-6′,7-dimethyl-5,5′,6,6′,7,7′,8,8′-octahy-dro-[1,2′-bianthracene]-9,9′,10,10′-tetraone); Alterporriol S ((2′S,3′R,4′S,6R,7S,9′R)-1,2′,3′,4,5′,6,7,8′-octahy-droxy-7′-methoxy-2′,4′,7-trimethyl-2′,3′,4′,4′a,5,6,7,8,9′,9′a-decahydro-[2,9′-bianthracene]-9,10,10′(1′H)-trione); (+)-aS-alterporriol C ((1S,5′S,6′R,7′S,8′R)-1′,2,5′,6′,7′,8,8′-heptahydroxy-3′,6-dimethoxy-3,6′-dime-thyl-5′,6′,7′,8′,8′a,10′a-hexahydro-[1,2′-bianthracene]-9,9′,10,10′-tetraone); Alterporriol C ((1S,5′R,6′S,7′R,8′S)-1′,2,5′,6′,7′,8,8′-heptahydroxy-3′,6-dimethoxy-3,6′-dime-thyl-5′,6′,7′,8′,8′a,10′a-hexahydro-[1,2′-bianthracene]-9,9′,10,10′-tetraone); Alterporriol N ((6R,6′R,7R,7′R,8R,8′R)-4,4′,6,6′,7,7′,8,8′-octahy-droxy-2,2′-dimethoxy-7,7′-dimethyl-5,5′,6,6′,7,7′,8,8′-octahydro-[1,1′-bianthracene]-9,9′,10,10′-tetraone); Alterporriol O ((2R,2′R,3S,3′S)-2,2′,3,3′,8,8′-hexahydroxy-6,6′-dimethoxy-3,3′-dimethyl-1,1′,2,2′,3,3′,4,4′-octahy-dro-[1,1′-bianthracene]-9,9′,10,10′-tetraone); Acetylalterporriol D ((1′S,5S,5′S,6R,6′R,7S,7′S,8R,8′R)-4,4′,5,5′,6′,7,7′,8,8′-nonahydroxy-2,2′-dimethoxy-7,7′-dimethyl-9,9′,10,10′-tetraoxo-5,5′,6,6′,7,7′,8,8′,9,9′,10,10′-dodecahydro-[1,1′-bianthracene]-6-yl acetate); Acetylalterporriol E ((1′R,5S,5′S,6R,6′R,7S,7′S,8R,8′R)-4,4′,5,5′,6′,7,7′,8,8′-nonahydroxy-2,2′-dimethoxy-7,7′-dimethyl-9,9′,10,10′-tetraoxo-5,5′,6,6′,7,7′,8,8′,9,9′,10,10′-dodecahydro-[1,1′-bianthracene]-6-yl acetate); Alterporriol D ((1S,5S,5′S,6R,6′R,7S,-7′S,8R,8′R)-4,4′,5,5′,6,6′,7,7′,8,8′-decahydroxy-2,2′-dimethoxy-7,7′-dimethyl-5,5′,6,6′,7,-7′,8,8′-octahy-dro-[1,1′-bianthracene]-9,9′,10,10′-tetraone); Alterporriol E ((1R,5S,5′S,6R,-6′R,7S,7′S,8R,8′R)-4,4′,5,5′,6,6′,7,7′,8,8′-decahydroxy-2,2′-dimethoxy-7,7′-dimethyl-5,5′,6,6′,7,7′,8,8′-octahy-dro-[1,1′-bianthracene]-9,9′,10,10′-tetraone); Stemphylanthranol A ((5S,5″S,6R,6″R,7S,7″S,8R,8″R)-2′,4,4″,5,5″,6,6″,7,7″,8,8′,8″-dodecahydroxy-2,2″,6′-trimethoxy-3′,7,7″-trimethyl-5,5″,6,6″,7,7″,8,8″-octahydro-[1,1′:5′,1″-teranthracene]-9,9′,9″,10,10′,10″-hexaone); Stemphylanthranol B ((5S,5″R,6R,6″R,7S,7″R,8R,8″R)-2′,4,4″,5,5″,6,7,7″,8,8′,8″-undecahydroxy-2,2″,6′-trimethoxy-3′,6″,7,7″-tetramethyl-5,5″,6,6″,7,7″,8,8″-octahydro-[1,1′:7′,1″-tetranthracene]-9,9′,9″,10,10′,10″-hexaone); 7-Chloroemodic acid; 7-Chloroemodinal; 7-Chloro-1,6,8-trihydroxy-3-methyl-10-anthrone; Damnacanthal (3-hydroxy-1-methoxy-anthraquinone-2-carboxaldehyde); 2,6-dihydroxy-anthraquinone; Austrocortinin (2-methoxy-7-methyl-1,4-dihydroxy-anthraquinone); Danthron (1,8-dihydroxy-anthraquinone); Dermolutein (8-methoxy-3-methyl-1,6-dihydroxy-anthraquinone-2-carboxylic acid); Fallacinal 3-formyl-6-methoxy-1,8-dihydroxy-anthraquinone); Phomarin (3-methyl-1,6-dihydroxy-anthraquinone); Anthragallol (alizarin brown; 1,2,3-trihydroxy-anthraquinone); Citreorosein (6-hydroxymethyl-1,3,8-trihydroxy-anthraquinone); Dermoglaucin (3-methyl-1,7,8-trihydroxy-6-methoxy-anthraquinone); Dermorubin (3-methyl-1,4,6-trihydroxy-8-methoxy-anthraquinone-2-carboxylic acid); Endocrocin (3-methyl-1,6,8-trihydroxy-anthraquinone-2-carboxylic acid); Erythroglaucin (3-methyl-1,4,8-trihydroxy-6-methoxy-anthraquinone); Flavokermesic acid (Laccaic acid D; 1-methyl-3,6,8-trihydroxy-anthraquinone-2-carboxylic acid); Flavopurpurin (alizarin Y; 1,2,6-trihydroxy-anthraquinone); Islandicin (2-methyl-1,4,5-trihydroxy-anthraquinone); Morindone (6-methyl-1,2,5-trihydroxy-anthraquinone); Rubrocristin (2-methyl-1,4,7-trihydroxy-5-methoxy-anthraquinone); Dermocybin (3-methyl-1,5,7,8-tetrahydroxy-6-methoxy-anthraquinone); and Kermesic acid (8-methyl-1,3,4,6-tetrahydroxy-anthra-quinone-7-carboxylic acid); 3-(beta-D-Glucopyranosyloxy)-1,6-dihydroxy-2-methyl-anthraquinone; 3-(6-O-Acetyl-beta-D-glucopyranosyloxy)-1,6-dihydroxy-2-methyl-anthraquinone; 3-[(2-O-6-Deoxy-alpha-L-mannopyranosyl-beta-D-glucopyranosyl)oxy]-1,6-dihydroxy-2-methyl-anthraquinone; 3-[(3-O-Acetyl-2-O-6-deoxy-beta-D-mannopyranosyl-beta-D-glucopyranosyl)oxy]-1,6-dihydroxy-2-methyl-anthraquinone; 3-[(6-O-Acetyl-2-O-6-deoxy-beta-D-mannopyranosyl-beta-D-glucopyranosyl)oxy]-1,6-dihydroxy-2-methyl-anthraquinone; 3-[(3,6-O-Diacetyl-2-O-6-deoxy-beta-D-mannopyranosyl-beta-D-glucopyranosyl)oxy]-1,6-dihydroxy-2-methyl-anthraquinone; 3-[(4,6-O-Diacetyl-2-O-6-deoxy-beta-D-mannopyranosyl-beta-D-glucopyranosyl)oxy]-1,6-dihydroxy-2-methyl-anthraquinone; 3-[(4-O-Acetyl-2-O-6-deoxy-beta-D-mannopyranosyl-beta-D-glucopyranosyl)oxy]-1,6-dihydroxy-2-methyl-anthraquinone; 3-[(6-O-Acetyl-2-O-beta-D-xylopyranosyl-beta-D-glucopyranosyl)oxy]-1,6-dihydroxy-2-methyl-anthraquinone; Ruberythric acid (1-Hydroxy-2-[(6-O-beta-D-xylopyranosyl-beta-D-glucopyranosyl)oxy]-anthraquinone); Lucidin primeveroside (1-Hydroxy-2-(hydroxymethyl)-3-[(6-O-beta-D-xylopyranosyl-beta-D-glucopyranosyl)oxy]-anthraquinone); 1-Acetyl-3-[(4-O-6-deoxy-beta-D-mannopyranosyl-beta-D-glucopy-ranosyl)oxy]-6-hydroxy-2-methyl-anthraquinone; 2-{[(6-O-beta-D-Glucopyranosyl-beta-D-glucopyranosyl)oxy]methyl}-11-hydroxy-anthraquinone; 3-[(2-O-6-Deoxy-beta-D-mannopyranosyl-beta-D-glucopyranosyl)oxy]-1-hydroxy-2-(methoxycarbonyl)-anthraquinone; 3-(beta-D-Glucopyranosyloxy)-2-(hydroxymethyl) anthraquinone; 3-(beta-D-Glucopyranosyloxy)-8-hydroxy-2-(hydroxymethyl)-anthraquinone; 2-(beta-D-Glucopyranosyloxy)-1,3-dihydroxy-anthraquinone; and 3-(beta-D-Glucopyranosyloxy)-1-hydroxy-2-(hydroxylmethyl)-anthraquinone.
38. The method according to claim 20, wherein the compound is selected from Formula (II) and wherein: R.sup.2 to R.sup.6 are each independently selected from the group consisting of H, Cl, Br, and F; R.sup.7 is selected from the group consisting of (i) —NH.sub.2, —NH(C.sub.1-10)alkyl, —OH, —CN; (ii) —O(C.sub.1-10)alkyl, or —O(C.sub.3-10)cycloalkyl; (iii) —COOH, —COO(C.sub.1-10)alkyl, —COO(C.sub.3-6)cycloalkyl, —COONH.sub.2, —COON((C.sub.1-10)alkyl).sub.2, or —COONH(C.sub.1-10)alkyl; and (iv) substituted or non-substituted (C.sub.3-6)heterocycle or (C.sub.7-10)carbo- or hetero-bicycle having 1 to 3 heteroatoms each independently selected from N, O and S; R.sup.8 is —C(═O)NH.sub.2 or —CN; R.sup.9 is selected from the group consisting of (i) —H, -Me, -Et, halogenor —CN; (ii) —COOH, —COO(C.sub.1-10)alkyl, —COO(C.sub.3-6)cycloalkyl, —COONH.sub.2, —COON((C.sub.1-10)alkyl).sub.2, or —COONH(C.sub.1-10)alkyl; (iii) —OH, —O(C.sub.1-10)alkyl, or —O(C.sub.3-10)cycloalkyl; (iv) substituted or non-substituted (C.sub.3-10)carbocycle; and c is0 or 1.
39. The method according to claim 38, wherein” R.sup.4 is Cl or F, and R.sup.2, R.sup.3, R.sup.5 and R.sup.6 are H or F; or R.sup.2 and R.sup.4 are Cl or F, and R.sup.3, R.sup.5 and R.sup.6 are H or F; R.sup.7 is selected from the group consisting of (i) —OMe and —OEt; (ii) —COOH, —COOMe or COOEt; and (iii) substituted or non-substituted heterobicycle having 1 nitrogen atom, isoindoline-1,3-dione, or ##STR00033## and R.sup.9 is selected from the group consisting of (i) —F; (ii) —COOH, —COOMe or COOEt; (iii) —OMe and —OEt; and (iv) (C.sub.3)carbocycle, (C.sub.5-6)carbocycle, aromatic (C.sub.6)carbocycle, non-substituted phenyl or phenyl substituted by a substituent selected from the group consisting of Cl, F, Br, substituted or non-substituted methyl, —(CF.sub.3), ethyl, propyl and cyclopropyl.
40. The method according to claim 20, wherein the compound is selected from the group consisting of ##STR00034## ##STR00035##
41. The method according to claim 20, wherein the nervous system disease or disorder is selected from the group consisting of: brain injuries; cerebrovascular diseases; consequences of cerebrovascular diseases; motor neuron disease; dementias; ALS; multiple sclerosis; traumatic brain injury; small-vessel cerebrovascular disease; familial forms of Alzheimer's Disease; sporadic forms of Alzheimer's Disease; vascular dementia; subcortical leukoencephalopathy and subcortical atherosclerotic encephalopathy; mixed forms of dementia; M. Parkinson; progressive supranuclear palsy and other forms of atypical parkinsonism; frontotemporal dementia; subcortical dementia; CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy); cerebral palsy; encephalitis lethargica; corticobasal degeneration; multiple system atrophy; chronic traumatic encephalopathy; Lytico-Bodig disease; FTDP-17; Parkinson linked to chromosome-17; diabetic neuropathy; symptoms of depression and depression-related symptoms, anhedonia,anorexia; schizophrenia with dementia; Korsakoff s psychosis; Lewy Body diseases; progressive supranuclear palsy; corticobasal degeneration; Pick's disease; Huntington's disease; thalamic degeneration; Creutzfeld-Jacob disease; HIV Dementia; disorders with mitochondrial dysfunction, neurodegenerative diseases of aging; cognitive-related disorder; mild cognitive impairment; age-associated memory impairment; age-associated cognitive decline; vascular cognitive impairment; central and peripheral symptoms of atherosclerosis and ischemia; atherosclerosis-related cardiovascular diseases; stroke; perivascular disease; renal dysfunction and renal failure; stress-related disorders; attention deficit disorders; attention deficit hyperactivity disorders; and memory disturbances in children.
42. The method according to claim 21, wherein the nervous system disease or disorder is selected from the group consisting of: brain injuries; cerebrovascular diseases; consequences of cerebrovascular diseases; motor neuron disease; dementias; ALS; multiple sclerosis; traumatic brain injury; small-vessel cerebrovascular disease; familial forms of Alzheimer's Disease; sporadic forms of Alzheimer's Disease; vascular dementia; subcortical leukoencephalopathy and subcortical atherosclerotic encephalopathy; mixed forms of dementia; M. Parkinson; progressive supranuclear palsy and other forms of atypical parkinsonism; frontotemporal dementia; subcortical dementia; CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy); cerebral palsy; encephalitis lethargica; corticobasal degeneration; multiple system atrophy; chronic traumatic encephalopathy; Lytico-Bodig disease; FTDP-17; Parkinson linked to chromosome-17; diabetic neuropathy; symptoms of depression and depression-related symptoms, anhedonia, anorexia; schizophrenia with dementia; Korsakoff s psychosis; Lewy Body diseases; progressive supranuclear palsy; corticobasal degeneration; Pick's disease; Huntington's disease; thalamic degeneration; Creutzfeld-Jacob disease; HIV Dementia; disorders with mitochondrial dysfunction, neurodegenerative diseases of aging; cognitive-related disorder; mild cognitive impairment; age-associated memory impairment; age-associated cognitive decline; vascular cognitive impairment; central and peripheral symptoms of atherosclerosis and ischemia; atherosclerosis-related cardiovascular diseases; stroke; perivascular disease; renal dysfunction and renal failure; stress-related disorders; attention deficit disorders; attention deficit hyperactivity disorders; and memory disturbances in children.
Description
[0267] The following Figures and Examples serve to illustrate the invention and are not intended to limit the scope of the invention as described in the appended claims.
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EXAMPLE 1
Materials and Methods
Animal Models and Generation of Tg-TOMM6 Mice
[0292] (a) Tg2576 mice (Taconic Biosciences, Rensselaer, N.Y., USA) with overexpression of human APP695 with the double mutation K670N/M671L were used as a genetic model of familial AD (FAD) (see Hsiao et al., Science 274, 99-103 (1996)). [0293] (b) Tg-TauP301L mice (Model 2508, Taconic Biosciences, Rensselaer, N.Y., USA) with neuron-specific expression of the most common FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation (Lewis et al., Nature Genetics 25, 402-405 (2000)). [0294] (c) To generate Tg-TOMM6 mice, the cDNA of TOMM6 was inserted into the SalI site of the CosSHa. Tet vector (InPro Biotechnology Inc. San Francisco, Calif., USA), which directs neuron-specific expression under control of the Syrian hamster prion protein (HaPrP) promoter (Hsiao et al., Science 274, 99-103 (1996), Scott et al., Protein Sci. 1, 986-997 (1992)). Plasmid sequences were removed by NotI digestion. The purified linear DNA (2 ng/microL) was injected into fertilized oocytes dissected out from super-ovulated mice (FVB or B6 (C57BL/6J) mice). For DNA injection, oocytes were kept in M2 medium. After DNA injection, injected embryos were transferred into M16 medium and incubated overnight in M16 medium in the presence of 10% CO.sub.2 at 37° C. in a humidified incubator. Thereafter, double-cell stage embryos were selected and transferred into the oviduct of pseudo-pregnant CD-1 foster mice. Pseudopregnancy was induced by overnight breeding with an infertile (vasectomized) male and detected by the presence of a vaginal plug. After birth, genomic DNA from F0 mice was isolated from ear punch biopsies taken at 3-4 weeks of age. Mice with stable genomic integration of the TOMM6 transgene were identified by genotyping PCR and used for further breeding. Tg-CMV-TOMM6 mice with transgenic TOMM6 expression under control of the ubiquitous CMV immediate-early promoter/enhancer were also generated, which directs ubiquitous expression of a transgene (Fu et al., J. Biol. Chem. 288, 7738-7766 (2013)). For ubiquitous expression, the cDNA coding for TOMM6 was inserted into EcoRI and XhoI sites of pcDNA3.1 plasmid; Thermo Fisher Scientific, Waltham, Mass., USA). Transgenic mice were generated as detailed above. [0295] (d) As a model, which reproduces major features of sporadic AD and depression, 15 months-old male rats (Sprague Dawley) were aged according to the CUMS protocol for 4 weeks. The following stimuli were administered each week in a random order: two periods (7 h and 17 h) of 45° cage tilt; soaked cage for 17 h; food deprivation (24 h) and water deprivation (12 h), twice a week; paired housing (17 h); overnight illumination during the dark phase, twice a week; noise (85 dB) in the room for 5 h, twice a week; flashing light (60 flashes/min) for 6 h, three times a week (AbdAlla et al., Biomed. Res. Int. 2015: 917156 (2015); El-faramawy et al., Pharmacol. Biochem. Behav. 91, 339-344 (2009)). The sucrose preference test (2% sucrose in water) was done immediately after a period of food and water deprivation. After four weeks of stress, more than 90% of untreated stressed rats showed signs of anhedonia, which was documented by a decreased sucrose consumption in the sucrose preference test 50% compared to non-stressed, age-matched control group and/or the stressed group treated with Compound-10F). As indicated, representative compounds (e.g. Compound-10F; 10 mg/kg body weight per day) were added to drinking water. The CUMS protocol was similarly performed with 12 months-old male Tg2576 mice for 3 months. [0296] (e) Extracts and compounds: As indicated, extract P1 from Galium aparine, extract P3 from Rubia cordifolia L., and small-molecule compounds (Compound-1, Compound-2, Compound-4, and Compound-7, Compound-10F: 10 mg/kg body weight/d) were added to drinking water. Compound-1 (alizarin; 1,2-dihydroxyanthraquinone) was purchased from Sigma (Sigma-Aldrich, St. Louis, Mo., USA), and Compound-2 (pseudopurpurin, purpurin-3-carboxylic acid) was isolated from Rubia tinctorum according to established protocols (Richter D., Biochem. J. 31, 591-595 (1937); Derksen et al., Phytochem. Anal. 15, 397-406 (2004)). Synthesis of Compound-4, Compound-7 and Compound-10F is described below. Plant extracts were made by decoction of dried plant material for 1 h in boiling water (200 g pulverized dried plant material/1 L water). For in vivo treatment, the plant extract was filtered, and the alizarin/anthraquinone content was adjusted to an amount of 0.05-0.1 mg/ml of alizarin by thin layer chromatography (TLC silica gel precoated plates 60F254 Merck, Darmstadt, Germany; mobile phase toluene/ethyl acetate/formic acid (70:25:5) or dichloromethane:methanol (9:1); visualization by visible light, UV 254 nm, 366 nm and/or by Bornträger reaction with KOH reagent (5-10% KOH in methanol)). For incubation with HEK cells, the plant extract was further concentrated by rotary evaporation to a final volume of 10 ml, filtrated and added to the cell culture medium (20 micro-l/10 ml medium). [0297] (f) Treatments: Treatment of the Tg2576 model was performed for six months without CUMS, or for three months (during the CUMS protocol), starting at an age of 12 months. Treatment of the Tg-TauP301L model was started at an age of 6 months and continued until 12 months. As a model, which reproduces major features of sporadic AD, aged 15 months-old male rats were subjected to the CUMS protocol for 4 weeks similarly as described (AbdAlla et al., Biomed. Res. Int. 2015: 917156 (2015)). All mice/rats were kept on a light/dark cycle of 12 h light/12 h dark, had free access to food and water (unless the CUMS protocol required a restriction) and were fed a standard rodent chow. At the end of the observation period, mice or rats were anesthetized (i.p.) with tribromoethanol (250 mg/kg) or urethane (1.2 g/kg), perfused intracardially with sterile PBS, and brains were isolated, and processed for histology or biochemical analyses. For protein extraction, hippocampi were dissected and immediately frozen in liquid nitrogen. All animal experiments were performed in accordance with NIH guidelines and approved by the local committees on animal experiments (University of Zurich Switzerland and Faculty of Veterinary Medicine, Cairo University).
Animal Model of Atherosclerosis
[0298] ApoE−/− mice (Taconic Biosciences, Rensselaer, N.Y., USA) with deficiency of apolipoprotein E (ApoE−/−) due to disruption of the endogenous ApoE gene were used as a genetic model of atherosclerosis (Piedrahita et al., Proc. Natl. Acad. Sci. U.S.A., 89, 4471-4475, 1992). Atherosclerotic lesion area was determined by quantitative image analysis with oil red O-stained aortas. Total plasma cholesterol was determined by a commercial kit (Sigma). Mice were kept on a 12 h dark and 12 h light cycle, had free access to food and water, and were fed a standard rodent chow (AIN-95-based diet without vitamin E supplementation and with 7% fat and 0.15% cholesterol). For the study, we used ApoE−/− mice on a B6 (C57BL/6J) background and non-transgenic B6 control mice. Alizarin treatment (10 mg/kg/day in drinking water) was initiated at an age of 4 weeks and continued for eight months until the end of the observation period. At an age of 9 months, mice were anesthetized (ketamine/xylazine, 100/10 mg/kg) and perfused intracardially with sterile PBS. Aortas were isolated, rapidly dissected free of adipose tissue on ice and immediately frozen in liquid nitrogen or processed for further use.
Clinical Study in Voluntary Research Participants
[0299] The study analyzed the treatment effect of topical administration of Compound-1 on warts. The study was performed according to the study protocol. Study design: The study was a phase-1, placebo-controlled study of Compound-1. The primary end-point was safety and tolerability. Secondary objectives were treatment effects on wart lesion size. The study included a cohort of 6 voluntary research participants (6 males; age 36-72 years; all Caucasians) with diagnosed flat warts. A total number of 94 lesions were treated with Compound-1. Vehicle-treated warts (n=88) of each participant served as placebo group. Study participants received once daily topical applications of a Compound-1-containing hydrogel (0.2%) or vehicle for 3 weeks. The study participants were under the medical supervision of Dr. Raafat Mahmood Fawzy (Clinical Director, Rabaa El Adaweya Medical Central Hospital, Cairo, Egypt). Clinical laboratory parameters of all research participants were within the normal range before, during the study and after completion of the study (observation period 4 weeks). There were no adverse effects in the study. Notably, there were no skin irritations, pain or other treatment-related adverse effects. The study protocol was conducted in accordance with the Declaration of Helsinki. All research participants provided written informed consent before participation. Research participants had the possibility to withdraw at any time from the study. But all participants wanted to complete the study.
Compound Synthesis
[0300] Compounds 3-10 and 10F were synthesized by EMC microcollections GmbH (Tübingen, Germany) and by ChiroBlock (Wolfen, Germany), according to established published protocols. Synthesis was performed by chemical synthesis methods, which were adapted from established protocols (for compound-3, compound-4, compound-5, compound-6: Singh et al., Organic Letters 14, 1198-1201 (2012); for compound-7, compound-8, compound-9, compound-10: Kaczanowska et al., J. Heterocyclic Chem. 48, 792 (2011), Kaczanowska et al., ACS Med. Chem. Lett. 1, 530-535 (2010)) and as detailed in
Antibodies
[0301] The following antibodies were used for immunoblotting and immunohistology: Abeta plaques were stained with monoclonal mouse antibody BAM-10 (crossreactive with residues 1-12 of the Abeta peptide, Sigma-Aldrich, St. Louis, Mo., USA); antibodies against AT2R (AGTR2) were raised in rabbit against an antigen encompassing amino acids 320-349 of the human AT2R (AGTR2) sequence (AbdAlla et al., J. Biol. Chem. 276, 39721-39726 (2001); J. Biol. Chem. 284, 6566-6574 (2009). HBsAg was detected with polyclonal antibodies raised against an antigen encompassing amino acids 1-20 of surface antigen HBsAg, and by a monoclonal HBsAg antibody produced in mouse (SAB4700767, Sigma-Aldrich, St. Louis, Mo., USA). Suitable antibodies for detection of HBsAg expression, aggregation and monomerization were also isolated from human blood from individuals undergoing vaccination against Hepatitis B. Antibodies against TOMM6 were raised in rabbit against a recombinant human TOMM6 protein (HPA004801, Sigma-Aldrich, St. Louis, Mo., USA); polyclonal antibodies were also raised in rabbit against a synthetic peptide encompassing amino acids 24-74 of human TOMM6 (ab205396; Abcam Cambridge, Mass., USA). PHF-Tau was detected with monoclonal AT8 antibody (MN1020; Thermo Fisher Scientific, Waltham, Mass., USA). Mouse monoclonal anti-NeuN antibody was raised against the neuron-specific protein NeuN (MAB377, clone A60, EMD Millipore, Merck KGaA, Darmstadt, Germany). Antibody against ATP6V1A was raised in rabbit against a recombinant fragment corresponding to amino acids 60-344 of human ATP6V1A (ab137574; Abcam, Cambridge, Mass., USA).
Immunohistochemistry
[0302] For Abeta plaque detection by immunohistology, paraffin-embedded brain sections (8 microm, 10-15 sections/brain taken at 30-50 microm intervals) were prepared from sham-treated Tg2576 mice (controls), and Tg2576 mice with 6 months of treatment with P3 extract and Compound-1, respectively. After antigen retrieval, sections were stained with monoclonal BAM-10 antibody (Sigma Aldrich, St. Louis, Mo., USA), which cross-reacts with residues 1-12 of the Abeta peptide. Plaque burden was analyzed by computerized quantitative image analysis (AbdAlla et al., Int. J. Mol. Sci. 14, 16917-16942 (2013)). Hyperphosphorylated Tau was detected with AT8 antibody on paraffin-embedded brain sections from 12 months-old Tg-TauP301L mice (Model 2508, Taconic Biosciences, Rensselaer, N.Y., USA) without and with treatment with P3 extract, and Compound-1 for 6 months.
Expression of HBsAg in Yeast
[0303] Recombinant HBsAg cDNA (synthesized by GeneScript, Piscataway, N.J., USA) was inserted into the expression vector p42K-TEF (D3011001-1 Dualsystems Biotech AG, Zurich). Yeast transformants were selected in the presence of G418 in the yeast growth medium (YPD; Bacto-yeast extract 10 g/L, Bacto-peptone 20 g/L and D-Glucose 20%). Yeast (Saccharomyces cerevisae) strain INVSc1 was used (Invitrogen GmbH, Nr. C810-00). After 3-4 days of cultivation to allow for protein expression, yeast cells were harvested by centrifugation, followed by washing with ice-cold PBS. The yeast cell pellet was immediately frozen at −70° C. Proteins were extracted for 30 min. at 4° C. with solubilization buffer (1% sodium deoxycholate, 0.1% SDS, 0.1% NP40, 5 mM EDTA, 50 mM Tris, pH 8.0) supplemented with protease/phosphatase inhibitors (Cat. No. P8349, and/or PPC1010, Sigma-Aldrich, St. Louis, Mo., USA). Particulate material was removed by centrifugation at 50 000×g for 20 min at 4° C. Solubilized proteins were concentrated and delipidated by precipitation with ice-cold acetone/methanol (12:2, final concentration 83%) for 90 min at 4° C. The pellet was dissolved in SDS-sample buffer supplemented with 2% SDS, 0.1 M DTT (or 5% mercaptoethanol), and 6 M urea for 90 min at room temperature. Proteins were stored at a concentration of 0.5 mg-1 mg/ml at −70° C. for further use. Protein were separated by urea-containing SDS-PAGE (7.5-10%) under reducing conditions, transferred to PVDF membranes by electrophoretic protein transfer in a tank transfer cell (Mini Trans-Blot cell, Bio-Rad GmbH, Munchen, Germany), and transferred HBsAg proteins were detected in immunoblot with HBsAg-specific antibodies raised in rabbit against an N-terminal epitope of HBsAg, or by a monoclonal HBsAg antibody produced in mouse (SAB4700767, Sigma-Aldrich, St. Louis, Mo., USA). Suitable antibodies for detection of HBsAg expression and aggregation were also isolated from human blood from individuals undergoing vaccination against Hepatitis B. Bound antibodies were visualized with F(ab).sub.2 fragments of enzyme-coupled secondary antibodies (Dianova GmbH, Hamburg, Germany), or by enzyme-coupled protein A (EMD Millipore, Merck KGaA, Darmstadt, Germany), and followed by enhanced chemiluminescent detection (ECL Prime, Amersham, GE Healthcare Life Sciences, Glattbrugg, Switzerland).
Nano-LC-ESI-MS/MS
[0304] To isolate Compound-1-interacting hippocampal proteins, hippocampi were isolated from 5-10 aged Tg2576 mice, pulverized under liquid nitrogen and solubilized for 30 min at 4° C. in solubilization buffer (1% sodium deoxycholate, 0.05% SDS, 0.05% Tween 20 in PBS, pH 7.4, supplemented with protease inhibitors). Insoluble material was removed by centrifugation. The supernatant was diluted 1:5 in PBS (supplemented with protease inhibitors). To this solubilisate, Compound-1 was added at a concentration of 10 μM. Buffer exchange into 20 mM Tris pH 7.4 was performed by centrifugation over Amicon Ultra Centrifugal Filter Units (MWCO 3 kDa; EMD Millipore Merck KGaA, Darmstadt, Germany). The concentrated proteins were dissolved in Laemmli sample buffer (Bio-Rad GmbH, Munchen, Germany) supplemented with mercaptoethanol (355 mM) and subjected to 8% SDS-PAGE under reducing conditions. Compound-1-interacting proteins were identified by co-migration, protein bands were cut and subjected to nano-LC-ES-MS/MS (performed by Proteome Factory AG, Berlin, Germany). Proteins were identified using MS/MS ion search of the Mascot search engine (Matrix Science, London, England) and nr protein database (National Center for Biotechnology Information, Bethesda, MD). Ion charge in search parameters for ions from ESI-MS/MS data acquisition were set to ‘1+, 2+, or 3+’ according to the common charge state distribution for the instrument and the method.
Immunoblot Detection of Proteins and Biochemical Analyses
[0305] Immunoblot detection of PHF-Tau in the hippocampus of stressed rats subjected to the CUMS protocol was performed with monoclonal PHF (AT8) antibody and the guanidine-hydrochloride-extracted hippocampal protein fraction (6.25 M guanidine hydrochloride in 50 mM Tris, pH 8.0). Proteins were separated by 8% urea-containing SDS-PAGE under reducing conditions. SDS-insoluble hippocampal contents of Abeta1-40 and Abeta1-42 were determined by ELISA after serial tissue extraction in the presence of protease inhibitors according to the protocol of the manufacturer (Invitrogen KHB3481 and KHB3441).
[0306] For immunoblot detection of (hippocampal or HEK cell) proteins, e.g. Tomm6/TOMM6 and Atp6v1a/ATP6V1A, (hippocampal) tissue was pulverized under liquid nitrogen, and HEK cell pellets were directly subjected to protein extraction. Proteins were extracted for 30 min at 4° C. with solubilization buffer (1% sodium deoxycholate, 0.1% SDS, 0.1% NP40, 5 mM EDTA, 50 mM Tris, pH 8.0) supplemented with protease/phosphatase inhibitors (Cat. No. P8349, and/or PPC1010, Sigma-Aldrich, St. Louis, Mo., USA). Particulate material was removed by centrifugation at 50 000×g for 20 min at 4° C. Solubilized proteins were concentrated and delipidated by precipitation with ice-cold acetone/methanol (12:2, final concentration 83%) for 90 min at 4° C. The pellet was dissolved in SDS-sample buffer supplemented with 2% SDS, 0.1 M DTT (or 5% mercaptoethanol), and 6 M urea for 90 min at room temperature. Proteins were stored at a concentration of 0.5 mg-1 mg/ml at −70° C. for further use. Immunoblot detection of proteins was performed with affinity-purified antibodies or F(ab).sub.2 fragments of the respective antibodies after separation of proteins by urea-containing SDS-PAGE (7.5%-10%) under reducing conditions and electrophoretic protein transfer to PVDF membranes in a tank transfer cell (Mini Trans-Blot cell, Bio-Rad GmbH, Munchen, Germany). Bound antibodies were visualized with F(ab).sub.2 fragments of enzyme-coupled secondary antibodies (Dianova GmbH, Hamburg, Germany) pre-absorbed to mouse serum proteins, or by enzyme-coupled protein A (EMD Millipore, Merck KGaA, Darmstadt, Germany) as applicable, and followed by enhanced chemiluminescent detection (ECL Plus, and/or ECL Prime, Amersham, GE Healthcare Life Sciences, Glattbrugg, Switzerland).
[0307] Proteins were also extracted from yeast cells and HEK cells expressing the indicated protein (i.e. HBsAg or AGTR2) as described above. Neuronal cell loss and hyperphosphorylated Tau in hippocampi of 15 months-old Tg2576 mice subjected to the CUMS protocol for 3 months was determined with crude homogenates of dissected hippocampi by direct binding assay with neuron-specific [.sup.125I]-labeled anti-NeuN antibody (MAB377, clone A60, EMD Millipore, Merck KGaA, Darmstadt, Germany) and [.sup.125I]-labeled AT8 antibody similarly as described (AbdAlla et al., J. Biol. Chem. 284, 6554-6565 (2009)).
Pharmacokinetic and Toxicology Studies in Rats and Dogs
[0308] Sub-chronic toxicity studies in dogs (German Shepherd dogs) and rats (Sprague Dawley rats) were performed by the Center of Applied Analytical and Veterinary Studies, Cairo, Egypt.
Measurement of Serum Level of Alizarin (Compound-1), Compound-7 and Compound-10F in Dogs and Rats
[0309] Serum concentrations of alizarin were determined with serum isolated from the blood of male and female German shepherd dogs (age: 8-9 months) taken at different time points (0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h) after oral intake of the indicated doses for 4 weeks. In addition, serum concentrations of alizarin (Compound-1) were determined in male and female Sprague Dawley rats (body weight: 200-250 g) treated for 1 month and/or three months by oral gavage of alizarin at a once daily dose of 100 mg/kg, 50 mg/kg, 25 mg/kg and 12.5 mg/kg. Serum proteins were removed by acetonitrile precipitation, and alizarin was extracted by chloroform before separation on an HPLC-C18 column (Poroshell 120 EC-C18, 3.0×50 mm, Agilent) with an HPLC system (Agilent 1100 Series) and detection at OD245 nm. For quantitative determination of Compound-7 and Compound-10F in rat and dog serum, serum proteins were also removed by acetonitrile precipitation before HPLC analysis as detailed above and detection at OD254 nm.
Fluorescence Spectrophotometry of AT2R-Cer and AT1R-Cer Expressed in HEK Cells
[0310] AT2R-Cer (AGTR2-Cerulean) is a fusion protein, in which full-length AGTR2 is fused C-terminally with a 5-Gly linker to the Cerulean variant (Cer) of the enhanced green fluorescent protein. The analogous construct of AGTR1-Cer, in which full-length AGTR1 is fused C-terminally with a 5-Gly linker to the Cerulean variant (Cer) of the enhanced green fluorescent protein, was generated in frame of a previous study (Quitterer et al., Biochem. Biophys. Res. Commun. 409, 544-549 (2011)). AGTR2-Cer and AGTR1-Cer were expressed in HEK cells with and without TOMM6 (cDNA coding for TOMM6 was inserted into EcoRI and XhoI sites of pcDNA3.1 plasmid;
Whole Genome Microarray Gene Expression Analysis of Aortic Genes
[0311] Whole genome microarray gene expression profiling was performed with aortic specimens isolated from 9-month-old ApoE−/− mice without treatment and with oral treatment for 8 months with alizarin (10 mg/kg/day), and untreated age-matched B6 control mice. Total RNA was isolated by the RNeasy Mini kit according to the protocol of the manufacturer (Qiagen). RNA purity was between 1.8 and 2 as determined by the absorbance ratio of 260/280. RNA quality and absence of signs of degradation were also controlled by RNA electrophoresis on a denaturing agarose gel by the presence of bright bands of 28S and 18S ribosomal RNA. Total RNA was processed for whole genome microarray gene expression profiling with the GeneChip One-Cycle Target Labeling System (Affymetrix) according to the protocol of the manufacturer (Affymetrix GeneChip Expression Analysis Technical Manual Rev. 5). Hybridization with the GeneChip (Mouse genome MG430 2.0 Array; Affymetrix) was done with 15 microg of fragmented cRNA in 200 microl of hybridization solution in a Hybridization Oven 640 (Affymetrix) at 45° C. for 16 h. Washing and staining of gene chips was done with the Affymetrix Fluidics Station 450 followed by scanning (Affymetrix GeneChip Scanner 7G). Signal processing was performed with GCOS (v. 1.4. Affymetrix). Data were scaled to a target value of 300. Probe sets (with call present and/or signal intensity ≥100) with significantly different signal intensity (p<0.05) indicative of different gene expression between different groups were identified by TIGR Multi Experiment Viewer (MeV v4.9).
EXAMPLE 2
Identification of a Plant Extract, which Inhibits Insoluble HBsAg Aggregation in Yeast
[0312] Screening approaches for AD-related protein aggregation processes often apply in vitro or cellular systems, which mimic pathological Abeta aggregation, e.g. by spontaneous aggregation of high concentrations of synthetic Abeta peptide(s) or over-expression of Abeta variants in cells (Shariatizi et al., Int. J. Biol. Macromol. 80, 95-106 (2015); Lee et al., Protein Sci. 18, 277-286 (2009)). But specific Abeta-targeting inhibitors were barely successful so far. Because protein aggregation follows overlapping rules and shares common mechanisms between different aggregation-prone proteins (Diaz-Villanueva et al., Int. J. Mol. Sci. 16, 17193-17230 (2015)), a non-Abeta-based protein aggregation assay system was established. The first system used HBsAg (hepatitis B virus major surface antigen), a protein, which forms high-molecular weight protein aggregates when over-expressed and assembled in yeast (Tleugabulova et al., J. Chromatogr. B. Biomed. Sci. Appl. 746, 153-166 (1999)). In this system, different plant extracts were tested, which were applied as media supplements during HBsAg expression in yeast. Among different plant extracts, the extract P1 from Galium aparine and P2 from the related Galium verum, inhibited HBsAg aggregation and promoted the appearance of monomeric HBsAg, which was demonstrated by immunoblot detection of HBsAg (
EXAMPLE 3
Plant Extracts from Galium Aparine and Galium Verum and Two Active Ingredients thereof Prevent AT2R Aggregation in HEK Cells
[0313] In the second non-Abeta-based protein aggregation assay, different plant extracts were tested in a mammalian cell system, which analyzed the protein aggregation of the angiotensin II AT2 receptor (AT2R, AGTR2) protein in human embryonic kidney (HEK) cells. The system has physiological relevance because this cellular system is capable to reproduce AT2R protein aggregation, which also occurs in brains of AD patients and AD animal models (AbdAlla et al., J. Biol. Chem. 284, 6554-6565 (2009); AbdAlla et al., J. Biol. Chem. 284, 6566-6574 (2009)). The AT2 receptor in human embryonic kidney (HEK) cells forms stable dimers/oligomers under pro-oxidant conditions, which are resistant to urea-containing reducing SDS-PAGE (
[0314] Subsequently, the active ingredient of the plant extracts P1 and P2 was investigated. Galium aparine and Galium verum of the Rubiaceae family are characterized specifically by the content of glycosides of colored anthraquinone derivatives, which upon hydrolysis generate alizarin and purpurin-3-carboxylic acid (=pseudopurpurin), and other related hydroxyanthraquinone compounds (Hill and Richter, J. Chem. Soc. 1714-1719 (1936); Hill and Richter, 1936, Proceedings of the Royal Society B, Biological Sciences, 547-560 (1936)). The content of anthraquinone dyes distinguishes the Galium genus from all other plant extracts, which were tested and which did not inhibit toxic protein aggregation in yeast and human cells. Therefore, alizarin (Compound-1) and pseudopurpurin (Compound-2) were tested in the cellular AT2R aggregation assay. Cultivation of HEK cells in the presence of Compound-1 (alizarin) and Compound-2 (pseudopurpurin) at a concentration of 10 microM for 72 h inhibited the aggregation of the AT2 receptor in human embryonic kidney cells (
EXAMPLE 4
The P1 Extract from Galium Aparine and Alizarin (Compound-1) Retard the Accumulation of SDS-Insoluble Abeta Peptides in the Hippocampus of Tg2576 AD Mice
[0315] The effects of the P1 extract from Galium aparine and Compound-1 (alizarin) were analysed in vivo, on insoluble hippocampal Abeta peptide accumulation and hippocampal contents of SDS-insoluble Abeta was determined in the Tg2576 AD mouse model (Hsiao et al., Science 274, 99-103 (1996)). Animals were treated for 6 months (age 12 months to 18 months) with extract P1 from Galium aparine, and Compound-1 (alizarin, 10 mg/kg/d), given in drinking water. The hippocampus was isolated and hippocampal contents of SDS-insoluble Abeta1-40 and Abeta1-42 peptides were quantified (
EXAMPLE 5
The P1 Extract from Galium Aparine and Alizarin (Compound-1) Retard PHF Tau Hyperphosphorylation and Neuronal Loss in Tg2576 AD Mice Subjected to the CUMS (Chronic Unpredictable Mild Stress) Protocol
[0316] The sole reduction of aggregated Abeta is not sufficient to reduce symptoms of AD in patients. Hyperphosphorylated PHF tau is a major factor, which promotes neurodegeneration in concert with aggregated Abeta peptides (Calderon-Garciduenas and Duyckaerts, Handb. Clin. Neurol. 145, 325-337 (2017)). To enhance PHF tau hyperphosphorylation and the process of neurodegeneration in the Tg2576 AD model, Tg2576 AD mice were subjected to the chronic unpredictable mild stress (CUMS) protocol (AbdAlla et al., J. Biol. Chem. 284, 6554-6565 (2009); Briones et al., Br. J. Pharmacol. 165, 897-907 (2012)). Hyperphosphorylated PHF-Tau was detected in the hippocampus of 15 months-old Tg-2576 mice after 3 months of CUMS (
[0317] In addition, the overt neuronal loss in the hippocampus of Tg2576 mice subjected to CUMS was also prevented by treatment with P1 extract from Galium aparine and alizarin (Compound-1) as determined by binding assay with [.sup.125I]-labeled anti-NeuN antibody (
EXAMPLE 6
Compound-1 (Alizarin) and P3 Extract from the Alizarin-Containing Rubia Cordifolia Retard Abeta Plaque Accumulation in Tg2576 Mice
[0318] Immunohistological analysis with Abeta-specific antibody BAM-10 confirmed that treatment with alizarin (Compound-1) significantly inhibited the accumulation of Abeta plaques in brains of aged 18-month-old Tg2576 mice compared to untreated 18-month-old Tg2576 AD controls (
[0319] In addition to the genus Galium from the rubiaceae family, the Rubia genus from the same family is also characterized by a high content of anthraquinones, notably alizarin and pseudopurpurin (Hill and Richter, 1936, Proceedings of the Royal Society B, Biological Sciences, 547-560 (1936)). Therefore, the treatment effect of extract P3 from Rubia cordifolia L was investigated. Treatment of Tg2576 AD mice for 6 months with extract P3 from Rubia cordifolia L. led to a highly decreased Abeta plaque load in hippocampal and brain cortical areas of Tg2576 AD mice (
EXAMPLE 7
Pseudopurpurin (Compound-2) and Extract P3 Retard Abeta Peptide Accumulation in Tg2576 Mice, and PHF Tau Hyperphosphorylation and Neuronal Loss in Tg2576 AD Mice Subjected to CUMS
[0320] The treatment effects of the P3 extract from Rubia cordifolia were compared with Compound-2 (pseudopurpurin) in the Tg2576 AD model because pseudopurpurin is another characteristic anthraquinone for the Galium and Rubia genera (Hill and Richter, 1936, Proceedings of the Royal Society B, Biological Sciences, 547-560 (1936)). Quantitative assessment of hippocampal contents of SDS-insoluble Abeta1-40 and Abeta1-42 peptides demonstrated that 6 months of treatment with extract P3 and Compound-2 both inhibit the accumulation of SDS-insoluble Abeta1-40 and Abeta1-42 in the hippocampus of 18-month-old Tg2576 mice (
[0321] In addition, the P3 extract and Compound-2 inhibited hippocampal PHF-Tau hyperphosphorylation in 15 months-old Tg-2576 mice induced by 3 months of CUMS (
EXAMPLE 8
The P3 extract from Rubia Cordifolia and Compound-1 Retard Tau Hyperphosphorylation in the Tg-TauP301L Model of Tauopathy
[0322] The anthraquinone-containing P1 and P3 extracts and two major anthraquinones, Compound-1 and Compound-2, decreased the hippocampal PHF-Tau content of Tg-2576 AD mice. It was investigated whether the P3 extract and Compound-1 also inhibited PHF-tau phosphorylation in a genetic model of tauopathy, the Tg-Tau-P301L mouse model with neuron-specific expression of the most common FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation (Lewis et al., Nature Genetics 25, 402-405 (2000)). Aged 12-month-old Tg-Tau-P301L mice without treatment showed substantial PHF-tau hyperphosphorylation in axons of the hippocampal CA3 area (
EXAMPLE 9: Identification of Tomm6 as an Interacting/Stabilizing Protein of Compound-1, Compound-2, and Extract P1 and P3 from Galium Aparine and Rubia Cordifolia
[0323] The major target of the prototypical anthraquinone, Compound-1 (alizarin) was searched for. To this end, a solubilisate of hippocampal proteins from aged Tg2576 mice supplemented with 10 microM Compound-1 was prepared, and the mixture was separated by SDS-PAGE under reducing conditions. The Compound-1-interacting proteins were identified by co-migration, cut from the gel, and subjected to protein identification. Nano-LC-ESI-MS/MS analysis identified Tomm6 (Mitochondrial import receptor subunit TOMM6 homolog) as a major Compound-1-interacting protein (
[0324] TOMM6 (Tom6) is an essential component of the TOM machinery, i.e. the multisubunit translocases in the outer mitochondrial membrane, which are required for the import of nucleus-encoded precursor proteins. It was investigated whether treatment with Compound-1, Compound-2, extract P1 and P3 from Galium aparine and Rubia cordifolia mediated protein stabilization of Tomm6 in the hippocampus of Tg2576 mice. Aged Tg2576 mice were treated for 6 months with Compound-1, Compound-2, P1 and P3 extract. Hippocampal protein contents of Tomm6 were determined in immunoblot. Immunoblot detection showed that the hippocampal protein content of Tomm6 in Tg2576 mice was substantially increased by treatment with Compound-1 (alizarin), Compound-2 (pseudopurpurin), P1 extract from Galium aparine, and P3 extract from Rubia cordifolia (
EXAMPLE 10
TOMM6 Enhances AT2R Protein Folding in Human Cells
[0325] It was found that Compound-1, Compound-2, extract P1 and extract P3 from the Galium and Rubia genera of the rubiaceae family interacted with and stabilized TOMM6. Next, it was analyzed whether stabilization/induction of TOMM6 was sufficient to exert cell/neuro-protection and prevented protein aggregation/misfolding of the AT2R (AGTR2) in HEK cells. Misfolded and aggregated AT2R promotes neurodegeneration whereas the intact AT2R could exert neuro-protection in AD models and patients (AbdAlla et al., J. Biol. Chem. 284, 6554-6565 (2009); AbdAlla et al., J. Biol. Chem. 284, 6566-6574 (2009); Quitterer and AbdAlla, Pharmacol. Res. pii: S1043-6618(18)31950-9 (2019)).
[0326] To analyze the effect of an increased cellular TOMM6 protein, the cDNA of TOMM6 was inserted into the EcoRI and XhoI sites of the expression plasmid pcDNA3.1, which enables transient and stable expression of a cDNA under control of the ubiquitous CMV immediate-early promoter/enhancer in cells and in vivo (
[0327] Upon expression in HEK cells, the total amount of cell membrane-localized AT2R-Cer was quantified in a fluorescence spectrophotometer. The co-expression of TOMM6 led to a significantly increased AT2R-Cer-specific fluorescence intensity, which is indicative of improved AT2R-Cer protein folding (
[0328] In contrast to AT2R-Cer, the related AT1R-Cer (AGTR1-Cerulean) was not increased by TOMM6 but AT1R-Cer was significantly decreased by TOMM6 (
EXAMPLE 11
Generation of Tg-TOMM6 Mice
[0329] The above data showed that increased protein levels of TOMM6 promoted the folding of the AT2R protein in human cells, which is misfolded and aggregated in brains of AD patients with sporadic AD (AbdAlla et al., J. Biol. Chem. 284, 6554-6565 (2009)). In addition, TOMM6 reduced the protein level of neurotoxic AT1R. To further validate the neuroprotective function of TOMM6 in vivo, transgenic mice with expression of TOMM6 under control of the neuron-specific hamster prion protein (HaPrP) promoter were generated. To generate Tg-TOMM6 mice, the cDNA of TOMM6 was inserted into the SalI site of the CosSHa. Tet vector (
[0330] To generate double-transgenic Tg-2576-TOMM6 mice, homozygous Tg-TOMM6 mice were crossed with heterozygous Tg2576 AD mice and double-transgenic Tg2576-TOMM6 mice were identified by genotyping PCR (sequences of primers used for genotyping PCR are derived from TOMM6-flanking CosSHa. Tet vector sequences and from the TOMM6 cDNA sequence) (
EXAMPLE 12
Transgenic TOMM6 Expression Retards Major Neuropathological Features in the Hippocampus of Tg2576 AD Mice
[0331] The goal was to investigate whether an increased TOMM6 level was sufficient to retard neurodegeneration in the Tg-2576 AD model. Aged 18 months-old double-transgenic Tg2576-TOMM6 mice had an increased hippocampal protein level of TOMM6 as determined in immunoblot compared to single-transgenic Tg2576 AD mice (
[0332] Double-transgenic Tg-2576-TOMM6 mice were used and it was analyzed whether an increased hippocampal TOMM6 protein level affected the neuropathological features in double-transgenic Tg2576-TOMM6 mice compared to single-transgenic Tg2576 controls. Hippocampal contents of SDS-insoluble Abeta1-40 and Abeta 1-42 were significantly decreased in double-transgenic Tg2576-TOMM6 mice compared to single-transgenic Tg2576 controls (
[0333] As detailed before, the Tg2586 AD model is largely devoid of major symptoms of clinical AD, i.e. neuronal loss and gross memory impairment (AbdAlla et al., J. Biol. Chem. 284, 6566-6574 (2009); Ashe and Zahs, Neuron 66, 631-645 (2010)). To enhance the process of neurodegeneration in Tg2576 AD mice, we subjected Tg2576 mice to chronic mild environmental stress (AbdAlla et al., J. Biol. Chem. 284, 6554-6565, (2009); Briones et al., Br. J. Pharmacol. 165, 897-907 (2012)), which is known to aggravate symptoms of dementia and neurodegeneration in patients (Peavy et al., Biol. Psychiatry 62, 472-478 (2007); Wilson et al., Neuroepidemiology 27, 143-163 (2006)). Quantitative analysis detected hyperphosphorylated PHF-Tau in the hippocampus of 15 months-old Tg-2576 mice after 3 months of CUMS (
[0334] Concomitantly, hippocampal neuronal loss was also prevented by transgenic TOMM6 expression, as determined by direct binding assay with [.sup.125I]-labeled anti-NeuN antibody (
EXAMPLE 13
Identification of TOMM6-Interacting (Inducing) Compounds Without Antioxidant Activity (FIG. 12 and FIG. 13)
[0335] TOMM6-inducing compounds were searched for and a screening system was established in HEK cells. HEK cells were cultured in the absence and presence of a test compound at a final concentration of 20 microM. Cells were harvested, proteins were extracted and TOMM6 protein levels were determined in immunoblot with TOMM6-specific antibodies. This assay identified compound 3-10 as TOMM6-interacting compounds and inducers of TOMM6 (
EXAMPLE 14
TOMM6-Interacting (Inducing) Compound-4 and Compound-7 Inhibit Symptoms of AD and Neurodegeneration in AD Model Mice
[0336] The TOMM6-interacting (inducing) Compound-4 and Compound-7 were selected for in vivo testing. Treatment with Compound-4 and Compound-7 led to a strong increase in hippocampal Tomm6 protein content of Tg2576 AD mice subjected to the CUMS protocol (
EXAMPLE 15
Emodin In Vivo Tests
[0337] Treatment with emodin (6-methyl-1,3,8 trihydroxyanthrachinone; formula is shown in
EXAMPLE 16
Structural Modifications of Alizarin
[0338] The scope of the present invention in general and for all embodiments also encompasses the therapeutic use of (e.g. nervous system diseases, neurodegenerative diseases, atherosclerosis and atherosclerosis-related diseases, as disclosed above) of (A) esters, ethers and amide derivatives of alizarin (Compound-1) and pseudopurpurin (Compound-2) to modulate pharmacokinetic properties and (B) glycosylated derivatives of alizarin and pseudopurpurin. Glycosylated derivatives of alizarin and pseudopurpurin can be isolated from alizarin- and pseudopurpurin-containing plants, and also can be synthesized, e.g. with bio-catalysed reactions applying glycosyltransferases (Ati et al., Beilstein J. Org. Chem. 13, 1857-1865, 2017). In addition, alizarin and other anthrachinone derivatives can be fed to recombinant E. coli as a substrate for biotransformation to generate alizarin-glucosides (Nguyen et al., Molecules 23, 2171, 2018). Alizarin is not a tumor promotor in mammalian cells and in vivo (Westendorf et al., Mutat. Res. 240, 1-12, 1990; Marec et al., Planta Med. 67, 127-131, 2001; Wölfle et al., Cancer Res. 50, 6540-6544, 1990; Poginsky et al., Carcinogenesis 12, 1265-1271, 1991). However, when tested in the Ames test with different Salmonella strains, alizarin could be mutagenic in the Salmonella strain TA1537 (Westendorf et al., Mutat. Res. 240, 1-12, 1990; Liberman D F et al., Applied and Environmental Microbiology 43, 1354-1359, 1982) and strain TA2637 (Tikkanen et al., Mutat. Res. 116, 297-304, 1983). The mutagenicity in bacteria is related to the hydroxyl groups of alizarin (Tikkanen et al., Mutat. Res. 116, 297-304, 1983). Anthrachinones with halogen substituents are not mutagenic (Brown JP and Brown RJ, Mutat. Res. 40, 203-224, 1976). Therefore, to minimize the potential risk of mutagenicity, the present invention in general and for all embodiments encompasses the use of all halogen- (e.g., F, Cl, Br)-substituted derivatives of the compounds described herein, preferably of alizarin and pseudopurpurin, more preferably fluorine-substituted derivatives and/or mimetics of alizarin and pseudopurpurin (see
EXAMPLE 17
Medical Uses of Alizarin for Supplementary Treatment and Prevention of Hepatitis B Virus Infection, and Treatment and Prevention of Human Papilloma Virus (HPV) Infection
[0339] The present invention in general and for all embodiments also encompasses the medical use of the compounds described herein, preferably alizarin (Compound-1), for preventive and supportive treatment of Hepatitis B infection because it was surprisingly found that not only plant extracts P1 and P2 (cf.
[0340] The present invention in general and for all embodiments also encompasses the medical use of the compounds described herein, preferably alizarin (Compound-1), for prevention and treatment of human papilloma virus (HPV) infections, in particular, because it was found that 3 weeks of once daily topical application of compounds according to the present invention, e.g. a Compound-1-containing hydrogel (0.2%), are an effective treatment for HPV-induced warts (see
[0341] Common warts greatly affect the quality of life of the patients, which can be attributed to the persistence and recurrence of warts. Malignant transformation usually develops in patients with genital warts and immunocompromised patients. Several high-risk HPV subtypes are associated with malignancies (e.g. HPV type 6, 11, 16, 18, 31, 35) and HPV type 5, 8, 20 and 47. This causal relationship between HPV infection and cancer raises concerns about the association between persistent HPV infection and the neoplastic progression of common warts to non-genital cancers, e.g. skin cancer (Lipke, 4, Clinical Medicine and Research, 273-293 (2006)). Warts are common and affect about 10% of the population worldwide. Currently, there is no cure for HPV infection and available treatments aim to eliminate symptoms. Treatment approaches include minor surgery, laser surgery, cryotherapy, peeling agents such as salicylic acid, medications (e.g. bleomycin, and imiquimod, which is an immunotherapy). Most treatment approaches are painful such as surgery, cryotherapy, laser therapy, and/or cause side effects such as burning and stinging and even may leave a scar. Even with treatment, warts tend to recur or spread. Therefore, there is an urgent need to improve the therapy and/or develop a new treatment approach for HPV.
EXAMPLE 18
Alizarin (Compound-1) Retards the Development of Atherosclerosis in ApoE-Deficient Mice as a Model of Atherosclerosis
[0342] Alzheimer's Disease (AD) is the most frequent form of dementia in the elderly. The second commonest form of dementia is vascular dementia (Appleton et al., Clin. Sci 131, 1561-1578, 2017). Often vascular dementia and AD coexist (ladecola, Neuron 80, 844-866, 2013). Atherosclerosis and ensuing cardiovascular disease are major risk factors for vascular dementia (Javanshiri et al., J. Alzheimers Dis. 65, 1247-1258, 2018). Cardiovascular risk factors are also considered to enhance AD pathology (Tublin et al., Circ. Res. 124, 142-149, 2019). Notably, atherosclerotic vascular lesions are causally related to the pathogenesis of vascular dementia, mixed forms of vascular dementia and even AD (Li et a., Chin. Med. J. (Engl) 131, 471-476, 2018). Cholesterol-lowering statin use reduces the risk of dementia in patients with stroke (Pan et al., J. Stroke Cerebrovasc. Dis. 27, 3001-3007, 2018). These data clearly indicate that atherosclerotic vascular disease is a contributor to dementia. However, there is an increasing concern that cholesterol-lowering treatment could enhance or even cause cognitive problems (Li et a., Chin. Med. J. (Engl) 131, 471-476, 2018). In view of this concern, it was investigated whether treatment with alizarin, which counteracts AD pathology, could interfere with atherosclerotic lesion development without altering plasma cholesterol levels. Alizarin (Compound-1) is a TOMM6/Tomm6 inducer, and TOMM6 induction restores the function of the angiotensin II type-2 receptor, AGTR2 (cf.
EXAMPLE 19
Pharmacokinetic Characterization of Alizarin (Compound-1) in Dogs and Rats
[0343] In view of the beneficial effects of alizarin (Compound-1) in murine AD and atherosclerosis animal models and the absent toxicity in the therapeutic dose range, further in vivo characterization of alizarin (Compound-1) was performed in dogs as a non-rodent animal model (
EXAMPLE 20
Sub-Chronic Toxicity Study of Alizarin in Rats Documents a Wide Therapeutic Index
[0344] The oral toxicity of alizarin (Compound-1) in rats was determined in a sub-chronic toxicity study. Rats were treated for 3 months with a once daily oral dose of alizarin of 25 mg/kg/day, 50 mg/kg/day and 100 mg/kg/day. The study did not find any significant adverse effects of alizarin up to a daily dose of 100 mg/kg/day regarding body weight, liver, heart and kidney weight, serum levels of calcium, creatinine, blood urea nitrogen (BUN), alanine transaminase (ALT) and aspartate aminotransferase (AST) (
EXAMPLE 21
Pharmacokinetic Data of Compound-7 in Dogs and Rats
[0345] Pharmacokinetic data of Compound-7 were determined as another representative TOMM6/Tomm6 inducer with a different chemical structure than alizarin (Compound-1). In dogs, Compound-7 showed peak serum concentrations of 3.96 microg/ml, 1.56 microg/ml and 0.59 microg/ml measured at t=1 h after drug intake after repeated once daily oral dosing of 12.5 mg/kg, 5 mg/kg and 2 mg/kg (
EXAMPLE 22
Development of Compound-10F
[0346] A series of compounds (i.e. Compounds 7-10) with a common 4-phenyl-2-methyl-pyridine-3-carboxamide backbone was identified as TOMM6/Tomm6 inducers (cf.
EXAMPLE 23
Pharmacokinetic Data of Compound-10F
[0347] The pharmacokinetic parameters of Compound-10F were determined. Compound-10F had oral bioavailability in vivo, in rats and dogs (
EXAMPLE 24
Compound-10F is a Tomm6 Inducer and Retards Symptoms of AD and Neurodegeneration In Vivo
[0348] It was investigated whether Compound-10F is also a Tomm6 inducer in vivo. Hippocampal contents of Tomm6 were determined of 15-month-old Tg2576 AD mice subjected to the CUMS protocol for 3 months by immunoblot. Upon treatment for three months with Compound-10 and Compound-10F during the CUMS protocol at a daily oral dose of 10 mg/kg/d, the hippocampal Tomm6 contents of treated Tg2576 AD mice were significantly higher than those of untreated Tg2576 AD controls (
EXAMPLE 25
Compound-10F Prevents Hippocampal PHF Tau Hyperphosphorylation and Peripheral Agtr2 Aggregation in the CUMS Model with Early Symptoms of Sporadic AD
[0349] The Tg2576 AD mouse model recapitulates major features of familial AD (FAD), which only encompasses 1-3% of all AD cases. The most frequent form of AD is the sporadic form of AD, which usually is not caused by a single disease-causing mutation (Quitterer and AbdAlla, Pharmacol Res. 2019 Apr. 13. pii: S1043-6618(18)31950-9). To recapitulate features of early sporadic AD, the CUMS model was used and aged, 15-month-old rats were subjected to 4 weeks of CUMS (AbdAlla et al., Biomed Res. Int. 2015:917156, 2015). Hippocampal contents of hyperphosphorylated PHF tau were strongly increased by 4 weeks of CUMS (