SUBSTITUTED RESORCYLIC ACID COMPOUNDS AS AMPK ACTIVATOR AND USES THEREOF

Abstract

The present invention relates to a substituted resorcylic acid compound having general formula I and compositions comprising said compound for use in the activation of AMPK. The compounds are useful for the treatment or prevention of a condition, disorder or disease related to type 2 diabetes, non-alcoholic fatty liver disease and/or obesity.

Claims

1. A method for the activation of AMPK comprising administering a compound having the general formula I to an individual in need of same, ##STR00027## wherein R1 and R3 are each independently selected from the group consisting of OH; OCH3; O-aliphatic saturated or unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; and a sulfate; R2 is selected from the group consisting of OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, and substituted and/or branched C4 to C20 polyalkynyl; R4 is selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a Cl, I, or F halogen atom; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, substituted and/or branched C4 to C20 polyalkynyl; R5 is selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, and substituted and/or branched C4 to C20 polyalkynyl, or a derivative or analogue thereof.

2. A method according to claim 1 wherein R1 and R3 are each independently selected from the group consisting of OH; OCH3; O-aliphatic saturated or unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; and a sulfate; R2 is selected from the group consisting of OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C10 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, and substituted and/or branched C4 to C20 polyalkynyl; R4 is selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a Cl, I, or F halogen atom; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, and substituted and/or branched C4 to C20 polyalkynyl; R5 is selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, and substituted and/or branched C4 to C20 polyalkynyl, or a derivative or analogue thereof.

3. A method according to claim 1 wherein R1 and R3 are each independently selected from the group consisting of OH; OCH3; O-aliphatic saturated or unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; and a sulfate; R2 is selected from the group consisting of OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C10 to C20 alkenyl; substituted and/or branched, C10 to C20 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, and substituted and/or branched C4 to C20 polyalkynyl; R4 is selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a Cl, I, or F halogen atom; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, and substituted and/or branched C4 to C20 polyalkynyl; R5 is selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; a sulfate; branched C1 to C20 alkyl; branched, C2 to C20 alkenyl; branched, C4 to C20 polyalkenyl; branched C2 to C20 alkynyl, or branched C4 to C20 polyalkynyl, or a derivative or analogue thereof.

4. A method according to claim 1 wherein R1 and R3 are each independently selected from the group consisting of OH; OCH3; O-aliphatic saturated or unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; and a sulfate; R2 is selected from the group consisting of OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, and substituted and/or branched C4 to C20 polyalkynyl; R4 is selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a Cl, I, or F halogen atom; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, and substituted and/or branched C4 to C20 polyalkynyl; R5 is selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a sulfate; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; substituted and/or branched, C4 to C20 polyalkenyl; substituted and/or branched C2 to C20 alkynyl, and substituted and/or branched C4 to C20 polyalkynyl, or a derivative or analogue thereof.

5. A method according to claim 1 wherein R1 and R3 are each independently selected from the group consisting of OH; OCH3; O-aliphatic saturated or unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; and a sulfate; R2 is selected from the group consisting of CH3, OH; O-glycoside; C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a chlorine; a CHO (aldehyde); a sulfate; substituted and/or branched, C2 to C15 alkenyl; or substituted and/or branched, C4 to C15 polyalkenyl; R4 is selected from the group consisting of H; CH3, OH; OCH3; a chlorine, and a 3,3-dimethylallyl chain (1h); R5 is selected from the group consisting of H; substituted and/or branched C1 to C20 alkyl; substituted and/or branched, C2 to C20 alkenyl; or substituted and/or branched, C4 to C20 polyalkenyl, or a derivative or analogue thereof.

6. A method according to claim 1 wherein R1 and R3 are each independently selected from the group consisting of OH; OCH3; O-aliphatic saturated or unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; and a sulfate; R2 is selected from the group consisting of OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; and a sulfate; a C5 isoprenoid chain selected from the group consisting of: 3-Methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1,1-dimethylallyl) (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), and 3-methyl-1,3-butadienyl (1p); a C10 isoprenoid chain selected from the group consisting of: 3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), and 5-methyl-2-(1-methylethyl)cyclohexyl (2o); a C15 isoprenoid chain selected from the group consisting of: 3,7,11-Trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), and 3-methyl-6-[5-(2-methyl-1-propen-1-yl)-3-furanyl]-2-hexen-1-yl (3d); a C20 isoprenoid chain selected from the group consisting of: 3,7,11,15-Tetramethylhexadecyl (phytanyl) (4a), and (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b); a (substituted) alkyl chain selected from the group consisting of: Methyl, ethyl, propyl, butyl, pentyl, heptyl, nonyl undecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), 2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylyethyl (7a), 2-hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), and 2-oxo-2-phenylethyl (11b); a (substituted) alkenyl chain selected from the group consisting of: ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), and 1-hydroxymethylene-2-oxopropyl (15a); and a substituted polyalkenyl chain selected from the group consisting of: 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), and a 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); R4 is selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a Cl, I, or F halogen atom; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a primary, secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; and a sulfate; a C5 isoprenoid chain selected from the group consisting of: 3-Methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1,1-dimethylallyl) (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), and 3-methyl-1,3-butadienyl (1p); a C10 isoprenoid chain selected from the group consisting of: 3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), and 5-methyl-2-(1-methylethyl)cyclohexyl (2o); a C15 isoprenoid chain selected from the group consisting of: 3,7,11-Trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), and 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d); a C20 isoprenoid chain selected from the group consisting of: 3,7,11,15-Tetramethylhexadecyl (phytanyl) (4a), and (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b); a substituted alkyl chain selected from the group consisting of: Methyl, ethyl, propyl, butyl, pentyl, heptyl, nonyl undecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), 2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylyethyl (7a), 2-hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), and 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2-oxo-2-phenylethyl (11b); a (substituted) alkenyl chain selected from the group consisting of: ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), and 1-hydroxymethylene-2-oxopropyl (15a); or a substituted polyalkenyl chain selected from the group consisting of: 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), and a 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); R5 is selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; a secondary, or tertiary amine; a primary or secondary amide; a cyano; a nitro; a sulfonate; and a sulfate; a C5 isoprenoid chain selected from the group consisting of: 3-Methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1,1-dimethylallyl) (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), and 3-methyl-1,3-butadienyl (1p); a C10 isoprenoid chain selected from the group consisting of: 3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), and 5-methyl-2-(1-methylethyl)cyclohexyl (2o); a C15 isoprenoid chain selected from the group consisting of: 3,7,11-Trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), and 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d); a C20 isoprenoid chain selected from the group consisting of: 3,7,11,15-Tetramethylhexadecyl (phytanyl) (4a), and (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b); a (substituted) alkyl chain selected from the group consisting of: Methyl, ethyl, propyl, butyl, pentyl, heptyl, nonyl undecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), 2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylyethyl (7a), 2-hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), and 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2-oxo-2-phenylethyl (11b); a (substituted) alkenyl chain selected from the group consisting of: ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), and 1-hydroxymethylene-2-oxopropyl (15a); and a substituted polyalkenyl chain selected from the group consisting of: 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), a 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a), and a derivative or analogue thereof.

7. A method according to claim 1 wherein R1 and R3 are each independently selected from the group consisting of OH; OCH3; O-aliphatic saturated or unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; and a sulfate; R2 is selected from the group consisting of OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; and a sulfate; a C5 isoprenoid chain selected from the group consisting of: 3-Methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1,1-dimethylallyl) (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), and 3-methyl-1,3-butadienyl (1p); a C10 isoprenoid chain selected from the group consisting of: 3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), and 5-methyl-2-(1-methylethyl)cyclohexyl (2o); a C15 isoprenoid chain selected from the group consisting of: 3,7,11-Trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), and 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d); a C20 isoprenoid chain selected from the group consisting of: 3,7,11,15-Tetramethylhexadecyl (phytanyl) (4a), and (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b); a substituted alkyl chain selected from the group consisting of: Methyl, ethyl, propyl, butyl, pentyl, heptyl, nonyl undecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), 2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylyethyl (7a), 2-hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), and 2-oxo-2-phenylethyl (11b); a substituted alkenyl chain selected from the group consisting of: ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), and 1-hydroxymethylene-2-oxopropyl (15a); and a (substituted) polyalkenyl chain selected from the group consisting of: 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), and 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); R4 is selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a Cl, I, or F halogen atom; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; and a sulfate; a C5 isoprenoid chain selected from the group consisting of: 3-Methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1,1-dimethylallyl) (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), and 3-methyl-1,3-butadienyl (1p); a C10 isoprenoid chain selected from the group consisting of: 3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), and 5-methyl-2-(1-methylethyl)cyclohexyl (2o); a C15 isoprenoid chain selected from the group consisting of: 3,7,11-Trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), and 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d); a C20 isoprenoid chain selected from the group consisting of: 3,7,11,15-Tetramethylhexadecyl (phytanyl) (4a), (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b); a (substituted) alkyl chain selected from the group consisting of: Methyl, ethyl, propyl, butyl, pentyl, heptyl, nonyl undecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), 2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylyethyl (7a), 2-hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), and 2-oxo-2-phenylethyl (11b); a (substituted) alkenyl chain selected from the group consisting of: ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), and 1-hydroxymethylene-2-oxopropyl (15a); and a (substituted) polyalkenyl chain selected from the group consisting of: 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), and 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); R5 is selected from the group consisting of H; OH; OCH3; O-glycoside; C-glycoside; acylated O-glycoside; acylated C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a halogen; a primary, secondary, or tertiary alcohol; a ketone; an aldehyde; an ester; and a sulfate; a C5 isoprenoid chain selected from the group consisting of: 3-Methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1,1-dimethylallyl) (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), and 3-methyl-1,3-butadienyl (1p); a C10 isoprenoid chain selected from the group consisting of: 3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), and 5-methyl-2-(1-methylethyl)cyclohexyl (2o); a C15 isoprenoid chain selected from the group consisting of: 3,7,11-Trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), and 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d); a C20 isoprenoid chain selected from the group consisting of: 3,7,11,15-Tetramethylhexadecyl (phytanyl) (4a), and (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b); a (substituted) alkyl chain selected from the group consisting of: Methyl, ethyl, propyl, butyl, pentyl, heptyl, nonyl undecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), 2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylyethyl (7a), 2-hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), and 2-oxo-2-phenylethyl (11b); a substituted alkenyl chain selected from the group consisting of: ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), and 1-hydroxymethylene-2-oxopropyl (15a); and a substituted polyalkenyl chain selected from the group consisting of: 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a), or a derivative or analogue thereof.

8. A method according to claim 1 wherein R1 and R3 are each independently selected from the group consisting of OH; OCH3; O-aliphatic saturated or unsaturated acyl, O-glycoside; acylated O-glycoside; sulfated O-glycoside; and a sulfate; R2 is selected from the group consisting of CH3, OH; O-glycoside; C-glycoside; sulfated O-glycoside; sulfated C-glycoside; a chlorine; a CHO (aldehyde); and a sulfate; a C5 isoprenoid chain selected from the group consisting of: 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1,1-dimethylallyl) (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), and 3-methyl-1,3-butadienyl (1p); a C10 isoprenoid chain selected from the group consisting of: 3,7-Dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), and 5-methyl-2-(1-methylethyl)cyclohexyl (2o); a C15 isoprenoid chain selected from the group consisting of: (2E,6E)-3,7,11-Trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), and 3-methyl-6-[5-(2-methyl-1-propen-1-yl)-3-furanyl]-2-hexen-1-yl (3d); and a (substituted) polyalkenyl chain selected from the group consisting of: 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a); R4 is H; CH3, OH; OCH3; a chlorine, or a 3,3-dimethylallyl chain (1h); and R5 is H; a C5 isoprenoid chain selected from the group consisting of: 3-Methylbutyl (1a), 4-hydroxy-3-methylbutyl (1b), 3-hydroxy-3-methylbutyl (1c), 2-hydroxy-3-methylbutyl (1d), (3,3-dimethyl-2-oxiranyl)methyl (epoxyprenyl) (1e), 2,3-dihydroxy-3-methylbutyl (1f), 3-methyl-2-oxobutyl (1g), 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h), 1,1-dimethyl-2-propen-1-yl (1,1-dimethylallyl) (1i), 3-methyl-1-buten-1-yl (1j), 4-hydroxy-3-methyl-2-buten-1-yl (1k), 1-hydroxy-3-methyl-2-buten-1-yl (1l), 3-hydroxy-3-methyl-1-butenyl (1m), 4-hydroxy-3-methylbut-1-en-1-yl (1n), 2-hydroxy-3-methyl-3-buten-1-yl (1o), and 3-methyl-1,3-butadienyl (1p); a C10 isoprenoid chain selected from the group consisting of: 3,7-Dimethyloctyl (tetrahydrogeranyl) (2a), 8-hydroxy-3,7-dimethyloctyl (2b), 3,7-dimethyloct-6-en-1-yl (citronellyl) (2c), 6,7-dihydroxy-3,7-dimethyl-octa-2-enyl (2d), [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e), 5-hydroxy-5-methyl-2-(1-methylethenyl)hexyl (2f), 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g), (2E)-3,7-dimethyl-2,6-octadien-1-yl (geranyl) (2h), (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i), 5-methyl-2-(1-methylethenyl)-4-hexen-1-yl (lavandulyl) (2j), 5-hydroxy-3,7-dimethyl-2,6-octadienyl (2k), 6-hydroxy-3,7-dimethyl-2,7-octadien-1-yl (2l), 3,7-dimethyl-7-hydroxy-2,5-octadienyl (2m), 3,7-dimethyl-5-oxo-2,6-octadienyl (2n), and 5-methyl-2-(1-methylethyl)cyclohexyl (2o); a C15 isoprenoid chain selected from the group consisting of: 3,7,11-Trimethyldodecyl (hexahydrofarnesyl) (3a), (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-yl (farnesyl) (3b), 7-hydroxy-3,7,11-trimethyl-2,10-dodecadien-1-yl (3c), and 3-methyl-6-[5-(2-methylprop-1-en-1-yl)furan-3-yl]hex-2-en-1-yl (3d); a C20 isoprenoid chain selected from the group consisting of: 3,7,11,15-Tetramethylhexadecyl (phytanyl) (4a), and (2E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-yl (geranylgeranyl) (4b); a (substituted) alkyl chain selected from the group consisting of: Methyl, ethyl, propyl, butyl, pentyl, heptyl, nonyl undecyl, pentadecyl, heptadecyl, eicosyl, hydroxymethyl (5a), 6-hydroxyheptyl (5b), 8-hydroxynonyl (5c), 12-hydroxytridecyl (5d), 2-hydroxytridecyl (5e), 2,12-dihydroxytridecyl (5f), 2-hydroxypentadecyl (5g), 14-hydroxypentadecyl (5h), 16-hydroxyheptadecyl (5i), 10-methoxyundecyl (5j), 12-methoxytridecyl (5k), 2-(acetyloxy)pentadecyl (5l), 2-(acetyloxy)-13-hydroxytridecyl (5m), 2-(acetyloxy)-12-hydroxytridecyl (5n), 2,12-bis(acetyloxy)tridecyl (5o), 2-(acetyloxy)tridecyl (5p), benzyl (6a), 2-phenylethyl (6b), 2-(4-hydroxyphenyl)ethyl (6c), 2-(3,4-dihydroxyphenyl)ethyl (6d), 2-(4-methoxyphenyl)ethyl (6e), 2-hydroxy-2-phenylyethyl (7a), 2-hydroxy-2-(2-hydroxyphenyl)ethyl (7b), tetrahydro-6-methyl-2H-pyran-2-yl)methyl (8a), 1,2-dioxopropyl (9a), 3-oxopentyl (9b), 2-oxopentyl (9c), 2-oxoheptyl (9d), 2-oxononyl (9e), 14-oxopentadecyl (9f), 2-oxotridecyl (9g), 1-hydroxy-2-oxopropyl (10a), 13-hydroxy-2-oxotridecyl (10b), 2-(4-hydroxyphenyl)-2-oxoethyl (11a), 2-oxo-2-phenylethyl (11b); a (substituted) alkenyl chain among the following representatives: ethenyl (12a), 1-propenyl (12b), 1-methylethenyl (12c), 1-methyl-1-propen-1-yl (12d), 8-pentadecen-1-yl (12e), 8-heptadecen-1-yl (12f), 10-heptadecen-1-yl (12g), 10-(acetyloxy)-8-pentadecenyl (13a), 2-phenylethenyl (14a), and 1-hydroxymethylene-2-oxopropyl (15a); or a (substituted) polyalkenyl chain selected from the group consisting of: 8,11-heptadecadien-1-yl (16a), 1-oxo-2,4-octadien-1-yl (17a), 4,6-dihydroxy-6-methyl-3-oxo-1,4-cyclohexadien-1-yl (17b), (6-methyl-4-oxo-4H-pyran-2-yl)methyl (17c), and 8-(3,4-dihydroxyphenyl)-4,7-octadien-1-yl (18a), or a derivative or analogue thereof.

9. A method according to claim 1 wherein R2 is hydrogen and R4 is not hydrogen.

10. A method according to claim 1 wherein R2 is hydrogen and R5 is not hydrogen.

11. A method according to claim 10 wherein R1 and R3 are each independently selected from the group consisting of OH; OCH3; O-glycoside; and a sulfate; R2 is selected from the group consisting of H; 3-methyl-2-buten-1-yl (3,3-dimethylallyl) (1h); and (2E)-3,7-dimethyl-2,6-octadien-1-yl (geranyl) (2h); R4 is H. R5 is selected from the group consisting of pentyl; benzyl (6a); 2-phenethyl (6b); and phenylethenyl (14a), and a derivative or analogue thereof.

12. A method according to claim 10 wherein R1 is selected from the group consisting of OH; O-glycoside; and a sulfate; R2 is selected from the group consisting of H; [3-methyl-3-(4-methyl-3-penten-1-yl)-2-oxiranyl]methyl (geranyl 2,3-epoxide) (2e); 3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl (2g); (2E)-3,7-dimethyl-2,6-octadien-1-yl (geranyl) (2h); (2Z)-3,7-dimethyl-2,6-octadien-1-yl (neryl) (2i); and 5-methyl-2-(1-methylethyl)cyclohexyl (2o); R3 is selected from the group consisting of OH; OCH3; O-glycoside; and a sulfate; R4 is H; R5 is selected from the group consisting of CH3; n-propyl, n-butyl, and pentyl, and a derivative or analogue thereof.

13. A method according to claim 1 wherein said compound of general Formula I is cannabidiolic acid, CAS number 1244-58-2.

14. A method according to claim 1 for the use to treat or prevent a condition, disorder, or disease related to type 2 diabetes, non-alcoholic fatty liver disease and/or obesity in a subject.

15. A method according to claim 1 wherein the activation of AMPK is through a direct activation mechanism.

16. A method according to claim 1 wherein the activation of AMPK is in muscle, liver and/or kidney tissues.

17. A method according to a claim 1 wherein the activation of AMPK is AMPK which comprises an 2 subunit, a 1 subunit, and a 1 subunit.

18. (canceled)

19. A method according to claim 1 for use in the preparation of a medicament for treating or preventing a condition, disorder, or disease responsive to AMPK activation.

20. (canceled)

21. A method according to claim 20, wherein the composition is a food, beverage, or dietary supplement.

22. A method according to claim wherein the composition further comprises a pharmaceutically acceptable carrier.

23-26. (canceled)

Description

BRIEF DESCRIPTION OF FIGURES

[0591] FIG. 1. Compound 1 increased the phosphorylation of the AMPK substrate, acetyl-CoA carboxylase (ACC), in U-2 OS Flp-In T-REx mammalian cells.

[0592] U-2 OS cells were treated with varying concentrations of compound 1 for 30 mins at 37 C. Phosphorylation of ACC was assessed using the HTRF Cisbio (pACC kit). Results are displayed as the average fold increase in activation (SEM) of 3 independent experiments. Compound 1 is 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6-pentylbenzoic acid, also known as Cannabidiolic acid, CAS number: 1244-58-2.

[0593] FIG. 2. Compound 1 did not activate AMPK in cells stably expressing an ADaM-binding site AMPK mutant (1 S108A).

[0594] The 1 WT or 1 S108A mutant were stably expressed in AMPK12 double knockout cells and treated with varying concentrations of Compound 1 for 30 mins at 37 C. Phosphorylation of ACC was assessed using the HTRF Cisbio (pACC kit). Results are displayed as the average fold increase in activation (SEM) of 3 independent experiments. Compound 1 is 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6-pentylbenzoic acid, also known as Cannabidiolic acid, CAS number: 1244-58-2.

[0595] FIG. 3. Compound 1 had impaired activation of AMPK in cells stably expressing the 2 isoform.

[0596] U-2 OS cells AMPK12 double knockout cells stably expressing AMPK 1 or 2 were treated with varying concentrations of Compound 1 for 30 mins at 37 C. Phosphorylation of ACC was assessed using the HTRF Cisbio (pACC kit). Results are displayed as the average fold increase in activation (SEM) of 3 independent experiments. Compound 1 is 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6-pentylbenzoic acid, also known as Cannabidiolic acid, CAS number: 1244-58-2.

[0597] FIG. 4. Compound 1 displays a dose-dependent inhibition of lipogenesis in primary mouse hepatocytes.

[0598] Primary hepatocytes, cells were seeded at 600 K cells per well in a 6-well plate overnight. Media was replaced with fresh M199 media alone for 2 hours prior to incubation with varying concentrations of compound 1 for 1 h at 37 C, in the presence of [1-14C]-acetate. The incorporation of [14C] into fatty acids was determined in the lower organic layer after separation from the aqueous phase. The results are displayed as the percentage of lipogenesis compared to the no treatment control.

[0599] Compound 1 is able to inhibit lipogenesis in a dose-dependent manner.

EXAMPLES

Example 1

Compound 1 Increased the Phosphorylation of the AMPK Substrate, Acetyl-CoA Carboxylase (ACC), in U-2 OS Flp-In T-REx Mammalian Cells.

[0600] Numerous studies have demonstrated that a wide-range of different natural compounds activate AMPK. Typically, natural compounds do not activate AMPK by directly binding to the enzyme, but instead indirectly activate AMPK due to the fact that they can cause perturbations in mitochondrial respiration. This leads to a decrease in ATP levels of the cell and activation of AMPK through AMP/ADP binding to the nucleotide-binding site of the AMPK 7 subunit.

[0601] In contrast, in the present invention, we have identified natural compounds that bind directly to AMPK through the allosteric drug and metabolite (ADaM) site formed at the interface between the AMPK and AMPK subunits. We have identified a new AMPK activator, which is part of the naturally occurring resorcylic acid chemical class, which directly activates AMPK in cells.

[0602] U-2 OS Flp-In T-REx cells were seeded at 50 K in a 96-well plate and left overnight at 37 C in DMEM GlutaMAX (Thermo Fisher Scientific) supplemented with 10% (vol/vol) FBS and 100 U/ml penicillin G, and 100 g/ml streptomycin. Cells were treated for 30 mins with varying concentrations of Compound 1 in media lacking FBS and then cells were lysed in 50 l of Cisbio lysis buffer #1 supplemented with blocking solution as per the manufacturer's protocol (Cisbio). Compound 1 is 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6-pentylbenzoic acid, also known as Cannabidiolic acid, CAS number: 1244-58-2.

[0603] Cells were lysed for 30 mins at room temperature before 16 l of lysate was incubated with 4 l of the HTRF antibodies (1:40 dilution of the acceptor and donor (p)ACC antibodies, as per the manufacturers protocol). Lysates were incubated overnight with the antibodies before 665 nm/620 nm ratio was determined using a MolecularDevices i3 plate reader (with a HTRF cartridge add-on).

[0604] FIG. 1 shows that using the pACC HTRF assay kit (Cisbio), compound 1 increases the phosphorylation of the AMPK substrate, ACC, in a dose-dependent manner in U-2 OS Flp-In T-REx mammalian cells. Phosphorylation of ACC is widely used as a cellular read-out of AMPK activation.

Example 2

In Cells, Compound 1 Did not Activate AMPK Complexes Containing a Mutation at the Allosteric Drug and Metabolite (ADaM) Site in Cells (S108A).

[0605] Next we investigated whether the ability of compound 1 to activate AMPK was mediated through its ability to directly bind to the ADaM-binding site. Compound 1 is 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6-pentylbenzoic acid, also known as Cannabidiolic acid, CAS number: 1244-58-2.

[0606] A MPK1/2 double knockout U-2 OS Flp-In T-Rex cell lines were generated by Horizon Discovery (Cambridge, UK). Cells were genotyped and analysed by western blotting to confirm that there was a complete knockout of AMPK1/2. We took these AMPK1/2 double knockout cells, and re-introduced the expression of human 1 wild-type (WT) or a 1 Serine 108 to alanine mutation (S108A). This was achieved using the Flp-In system (Invitrogen) present in this cell line and stable cells expressing 1 WT or a 1 S108A mutant were generated according to the manufacturers' protocols. Re-expression of the 1 subunit was confirmed by western blot analysis. Mutation of 1 S108A has previously been shown to interfere with regulation of AMPK by compounds binding to the allosteric drug and metabolite (ADaM) binding site formed at the interface between the subunit carbohydrate binding module (CBM) and the a subunit kinase domain. In contrast, activators through work through nucleotide binding in the AMPK subunit can still regulate the 1 S108A mutant comparable to 1 WT activation.

[0607] Cells stably expressing 1 WT or a 1 S108A mutant were treated with varying concentrations of Compound 1 and subjected to the pACC HTRF (Cisbio) assay to determine the level of phosphorylation of the AMPK substrate, ACC, in cell lysates, as in example 1. As shown in FIG. 2, Compound 1 was able to dose-dependently increase pACC in cells stably expressing the 1 WT subunit. In contrast, Compound 1 was not able to increase pACC in cells expressing the 1 S108A mutant. This suggests that Compound 1 activates AMPK by binding to the ADaM pocket of AMPK.

Example 3

In Cells, Compound 1 Impaired Activation of 2-Containing AMPK Complexes.

[0608] We took AMPK1/2 double knockout cells, and re-introduced the expression of human 31 WT or 2 WT isoforms. Re-expression of the 1 and 2 subunits was confirmed by Western blot analysis and were shown to be expressed to a similar extent. Cells stably expressing 1 WT or 2 were treated with varying concentrations of compound 1 and subjected to the pACC HTRF (Cisbio) assay to determine the level of phosphorylation of the AMPK substrate, ACC, in cell lysates, as in example 1. As shown in FIG. 3, compound 1 was able to dose-dependently increase pACC in cells stably expressing 1 WT. In contrast, there was an impaired ability of compound 1 to increase pACC in cells expressing the 2 WT isoform. This activation profile is characteristic of activators that bind to the ADaM site and consistent with previous studies showing that ADaM-site activators have poorer activation of 2-containing complexes in vitro and in cells. Taken together, we show that in cells, compound 1 activates AMPK by binding to the ADaM pocket of AMPK separate from the nucleotide-binding site in the AMPK subunit.

[0609] Taken together, we show for the first time that a new resorcylic acid compound (compound 1), activates AMPK by binding to the ADaM pocket of AMPK, which is separate from the nucleotide-binding site in the AMPK subunit. Compound 1 is 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6-pentylbenzoic acid, also known as Cannabidiolic acid, CAS number: 1244-58-2.

Example 4: Compound 1 Displays a Dose-Dependent Inhibition of Lipogenesis in Primary Hepatocytes

[0610] Hepatocyte isolation: The liver was first perfused with 50 ml perfusion buffer (Krebs-Hepes buffer with 0.5 M EDTA), followed with 50 ml collagenase A buffer (Krebs-Hepes buffer with 5 mM CaCl.sub.2) and 0.5 mg/ml collagenase). After passage through a 100 m mesh, the cell solution was washed several times with cold media and finally the cell culture pellet was resuspended in culture medium (medium 199 (M199)+GlutaMAX, 100 U/ml penicillin G, and 100 g/ml streptomycin, 0.1% (wt/vol) BSA, 10% FCS, 10 nM insulin, 200 nM triiodothyronine and 500 nM dexamethasone). Hepatocytes were left to attach (3-4 h) and cultured overnight in M199 supplemented with antibiotics and 100 nM dexamethasone. Cells were used for experiments the following morning.

[0611] For lipogenesis measurements in primary hepatocytes, cells were seeded at 600 K cells per well in a 6-well plate overnight. Media was replaced with fresh M199 media alone for 2 hours prior to incubation with varying concentrations of compound 1 for 1 h at 37 C, in the presence of [1-14C]-acetate. The incorporation of [14C] into fatty acids was determined in the lower organic layer after separation from the aqueous phase. The results are displayed as the percentage of lipogenesis compared to the no treatment control.

[0612] Lipogenesis is controlled by the AMPK substrate ACC, and phosphorylation and inhibition of ACC by AMPK, leads to a decrease in lipogenesis. Lipogenesis was measured in primary hepatocytes by determining the incorporation of 14C-labelled acetate into fatty acids. Lipogenesis was monitored in the presence or absence of varying concentrations of compound 1 for 1 h at 37 C. The results shown in FIG. 4, show that compound 1 is able to inhibit lipogenesis in a dose-dependent manner. This observation is consistent with its ability to activate AMPK in hepatocytes, which leads to the phosphorylation and inhibition of ACC. These data are also consistent with the ability of compound 1 to activate AMPK in both a cell line and primary hepatocytes.