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DAPHNANE DITERPENOID RESISTANT TO PROSTATE CANCER AND PREPARATION METHOD THEREOF

20230159551 · 2023-05-25

    Inventors

    Cpc classification

    International classification

    Abstract

    The invention relates to a daphnane diterpenoid resistant to a prostate cancer and a preparation method thereof. A daphnane diterpenoid compound as represented by formula (I) or formula (II) significantly inhibits the proliferation of various prostate cancer cells; the activities of some such compounds at a cellular level and an animal level are higher than that of the existing clinical targeting drug enzalutamide; and the daphnane diterpenoid compounds have strong synergistic effects when used in combination with the enzalutamide and are expected to become candidate drugs for treatment or adjuvant treatment of a castration-resistant prostate cancer.

    ##STR00001##

    Claims

    1. A daphnane diterpenoid compound of formula I or formula II: ##STR00024## wherein: in the formula I and the formula II, a bond between C-1 and C-2 is a single or double bond, a bond between C-6 and C-7 is a single or double bond, and a bond between C-15 and C-16 is a single or double bond; in the formula I and the formula II, R.sub.1 is hydrogen or hydroxyl or R.sub.1 is absent when a double bond is formed between C-1 and C-2; in the formula I and the formula II, R.sub.2 is hydrogen, hydroxyl, carbonyl, benzoyl, or acetyl; in the formula I and the formula II, R.sub.3 is hydrogen, hydroxyl, acetyl, isovaleryl, crotonyl, or benzoyl; in the formula I and the formula II, R.sub.4 is hydrogen, hydroxyl, acetyl, isobutyryl, 2-thienylcarbonyl, benzoyl, or palmitoyl; in the formula I and the formula II, R.sub.5 is hydroxyl, fluorine, chlorine, bromine, or iodine, or forms a ternary epoxy with R.sub.6 or R.sub.6 is absent when a double bond is formed between C-6 and C-7; in the formula I and the formula II, R.sub.6 is hydrogen, hydroxyl, fluorine, chlorine, bromine, or iodine, or forms a ternary epoxy with R.sub.5 or R.sub.5 is absent when a double bond is formed between C-6 and C-7; in the formula I, R.sub.7 is methyl, phenyl, nonanyl, (1E, 3E)-nonadienyl, (1E, 3Z)-nonadienyl, or (1E, 3E, 5E)-nonatrienyl; in the formula II, R.sub.7 is hydrogen, benzoyl, acetyl, decanoyl, (2E, 4E)-decadienoyl, (2E, 4Z)-decadienoyl, or (2E, 4E, 6E)-decatrienoyl; in the formula I and the formula II, R.sub.8 is hydrogen or hydroxyl or R.sub.8 is absent when a double bond is formed between C-15 and C-16; and in the formula I and the formula II, R.sub.9 is hydrogen, hydroxyl, acetyl, benzoyl, isobutyryl, butyryl, or propionyl.

    2. The daphnane diterpenoid compound according to claim 1, wherein the daphnane diterpenoid compound is selected from the group consisting of: a compound of formula (III): ##STR00025## wherein the compound of formula (III) is selected from the group consisting of: TABLE-US-00006 Compound R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.7 R.sub.8 R.sub.9 YH-1 Δ1 ═O OH OH Ph Δ16 OBu YH-2 Δ1 ═O OH OH Ph Δ16 OiBu YH-3 Δ1 ═O OH OH Ph Δ16 OProp YH-4 Δ1 ═O OH OH Ph Δ16 OH YH-5 Δ1 ═O OH OG Ph Δ16 OAc YH-6 Δ1 ═O OH OH Ph Δ16 OAc YH-7 Δ1 ═O OAc OAc Ph Δ16 OAc YH-8 Δ1 ═O OH OAc Ph Δ16 OAc YH-9 Δ1 ═O OH OBz Ph Δ16 OAc YH-10 Δ1 ═O OH OS Ph Δ16 OAc YH-11 Δ1 ═O OH OH Ph Δ16 OBz YH-12 Δ1 ═O OAc OAc Ph Δ16 OBz YH-13 Δ1 ═O OH OAc Ph Δ16 OBz YH-14 Δ1 ═O OH OH A Δ16 OH YH-15 Δ1 ═O OH OH A Δ16 OBu YH-16 Δ1 ═O OH OH A Δ16 OBz YH-17 Δ1 ═O OH OH D Δ16 OBz YH-18 Δ1 ═O OAc OAc A Δ16 OBz YH-19 Δ1 ═O OH OAc A Δ16 OBz YH-20 Δ1 ═O OH OBz A Δ16 OBz YH-21 Δ1 ═O OH OS A Δ16 OAc YH-22 Δ1 ═O OH OH A Δ16 OAc YH-23 Δ1 ═O OAc OAc A Δ16 OAc YH-24 Δ1 ═O OH OAc A Δ16 OAc YH-25 Δ1 ═O OH OBz A Δ16 OAc YH-26 Δ1 ═O OH OS A Δ16 OAc YH-27 Δ1 ═O OH OG A Δ16 OAc YH-28 Δ1 ═O OH OG D Δ16 OBz YH-29 Δ1 ═O OH OH B Δ16 OBz YH-30 Δ1 ═O OH OH Me Δ16 OAc YH-31 Δ1 ═O OH OH B Δ16 OAc YH-32 Δ1 ═O OH OH D Δ16 OAc YH-33 Δ1 ═O OH OH F Δ16 OAc YH-34 Δ1 ═O OH OH F Δ16 OBz YH-35 αH ═O OH OH Ph Δ16 OAc YH-36 αH ═O OH OH Ph Δ16 OBz YH-37 Δ1 ═O OH OH Da H OAc YH-38 αH ═O OH OH Da H OAc YH-39 αH ═O OH OH Ph H OBz YH-40 Δ1 ═O OH OH Ph H OBz YH-41 Δ1 ═O OH OH Ph Δ16 H YH-42 αH βO(CO)E OH OH Ph Δ16 H YH-43 αH βOH OH POE Ph Δ16 H; a compound of formula (IV): ##STR00026## wherein the compound of formula (IV) is selected from the group consisting of: TABLE-US-00007 Compound R.sub.3 R.sub.4 R.sub.5 R.sub.6 R.sub.7 R.sub.9 YH-44 H OH Δ6 H Me OBz YH-45 OH OBz βCl αOH Ph OAc YH-46 OH OBz αOH βCl Ph OAc YH-47 OH OH βCl αOH Ph OAc YH-48 OH OH αOH βCl Ph OAc YH-49 OH OH βCl αOH Ph OBz YH-50 OH OH αOH βCl Ph OBz YH-51 OH OH αOH αOH Ph OBz YH-52 OH OH βBr αOH Ph OBz YH-53 OH OH αOH βBr Ph OBz; a compound of formula (V): ##STR00027## wherein the compound of formula (V) is selected from the group consisting of: TABLE-US-00008 Compound R.sub.7 R.sub.9 YH-54 COA OAc YH-55 COA OBz YH-56 Bz OBz;  and a compound of formula (VI): ##STR00028## wherein the compound of formula (VI) is selected from the group consisting of: TABLE-US-00009 Compound R.sub.7 R.sub.9 YH-57 H OBz YH-58 H OAc YH-59 COD OAc YH-60 Bz OBz YH-61 COA OH YH-62 COA OAc YH-63 COA OBz YH-64 COA H;  and wherein in formula (III), formula (IV), formula (V), and formula (VI): ##STR00029## Δ1 is when R.sub.1 is absent and a double bond is formed between C-1 and C-2; Δ6 is when R.sub.5 is absent and a double bond is formed between C-6 and C-7; Δ16 is when R.sub.8 is absent and a double bond is formed between C-15 and C-16; and α is when the identified substituent is on the opposite face of the hydroxyl group of the contiguous ring; and β is when the identified substituent is on the same face as the hydroxyl group of the contiguous ring.

    3. The daphnane diterpenoid compound according to claim 2, wherein the daphnane diterpenoid compound is selected from the group consisting of YH-6, YH-11, YH-16, YH-17, YH-22, YH-35, YH-36, YH-47, YH-48, YH-49, YH-50, YH-52, and YH-53.

    4. The daphnane diterpenoid compound according to claim 1, wherein the daphnane diterpenoid compound is a pharmaceutically acceptable derivative thereof.

    5. The daphnane diterpenoid compound according to claim 4, wherein the pharmaceutically acceptable derivative is a salt thereof.

    6. A composition comprising at least one daphnane diterpenoid compound according to claim 1 and/or a pharmaceutically acceptable derivative thereof.

    7. A composition comprising at least one daphnane diterpenoid compound selected from the group consisting of YH-8, YH-9, YH-10, YH-19, YH-20, YH-21, YH-24, YH-25, YH-26, YH-30, YH-33, YH-34, YH-37, YH-38, YH-39, YH-45, YH-46, YH-47, YH-48, YH-49, YH-50, YH-52, YH-53, YH-56, YH-57, YH-60, and YH-61 according to claim 2 and/or a pharmaceutically acceptable derivative thereof.

    8. A composition for treatment or adjuvant treatment of a castration-resistant prostate cancer, comprising at least one daphnane diterpenoid compound according to claim 1, or a pharmaceutically acceptable derivative thereof.

    9. A composition for treatment or adjuvant treatment of a castration-resistant prostate cancer, comprising at least one daphnane diterpenoid compound selected from the group consisting of YH-6, YH-11, YH-16, YH-17, YH-22, YH-35, YH-36, YH-8, YH-9, YH-10, YH-19, YH-20, YH-21, YH-24, YH-25, YH-26, YH-30, YH-33, YH-34, YH-37, YH-38, YH-39, YH-45, YH-46, YH-47, YH-48, YH-49, YH-50, YH-52, YH-53, YH-56, YH-57, YH-60, and YH-61 according to claim 2, or a pharmaceutically acceptable derivative thereof.

    10. The composition according to claim 9, further comprising at least one compound having a therapeutic effect on a castration-resistant prostate cancer.

    11. A method for treatment or adjuvant treatment of a castration-resistant prostate cancer in a patient, comprising: determining whether the patient suffers from the castration-resistant prostate cancer; and administering to the patient a therapeutic amount of a daphnane diterpenoid compound according to claim 1 or a pharmaceutically acceptable salt, a solvate, or a co-crystal thereof.

    12. The method according to claim 11, further comprising administering to the patient at least one compound having a therapeutic effect on the castration-resistant prostate cancer.

    13. The method according to claim 12, wherein the compound having the therapeutic effect on the castration-resistant prostate cancer is selected from the group consisting of enzalutamide, abiraterone, cyclophosphamide, adriamycin, docetaxel, mitoxantrone, and combinations thereof.

    14. The composition according to claim 8, wherein the composition further comprises at least one compound having a therapeutic effect on a castration-resistant prostate cancer.

    15. The composition according to claim 14, wherein the compound having the therapeutic effect on the castration-resistant prostate cancer is selected from the group consisting of enzalutamide, abiraterone, cyclophosphamide, adriamycin, docetaxel, mitoxantrone, and combinations thereof.

    16. The composition according to claim 10, wherein the compound having the therapeutic effect on the castration-resistant prostate cancer is selected from the group consisting of enzalutamide, abiraterone, cyclophosphamide, adriamycin, docetaxel, mitoxantrone, and combinations thereof.

    17. A method for treatment or adjuvant treatment of a castration-resistant prostate cancer in a patient, comprising administering to a patient in need thereof a therapeutic amount of the composition according to claim 8.

    18. The method according to claim 17, further comprising administering to the patient at least one compound having a therapeutic effect on the castration-resistant prostate cancer.

    19. A method for treatment or adjuvant treatment of a castration-resistant prostate cancer in a patient, comprising administering to a patient in need thereof a therapeutic amount of the composition according to claim 9.

    20. The method according to claim 19, further comprising administering to the patient at least one compound having a therapeutic effect on the castration-resistant prostate cancer.

    Description

    BRIEF DESCRIPTION OF THE DRAWINGS

    [0041] FIG. 1 is a flowchart showing the extraction and isolation of daphne genkwa.

    [0042] FIG. 2A shows the effect of oral administration of Compound YH-52 on the size of tumor.

    [0043] FIG. 2B shows the effect of oral administration of Compound YH-52 on the volume of tumor.

    [0044] FIG. 2C shows the effect of oral administration of Compound YH-52 on the weight of tumor.

    [0045] FIG. 3A shows the inhibitory effect of intraperitoneal injection administration of Compound YH-52 combined with enzalutamide on prostate cancer cells 22RV1.

    [0046] FIG. 3B shows the effect of intraperitoneal injection administration of Compound YH-52 combined with enzalutamide on the size of tumor.

    [0047] FIG. 3C shows the effect of intraperitoneal injection administration of Compound YH-52 combined with enzalutamide on the volume of tumor.

    [0048] FIG. 3D shows the effect of intraperitoneal injection administration of Compound YH-52 combined with enzalutamide on the weight of tumor.

    DETAILED DESCRIPTION

    [0049] Thirty-four (34) natural daphnane diterpenoids were isolated by the inventors from thymelaeaceae plants, daphne genkwa, and 30 derivatives were obtained from some compounds after being carried out with a structural modification. Relevant tests on the obtained series of diterpenoids for resisting to prostate cancer cells found a series of compounds that have a significant inhibitory activity on tumor cells and a stronger effect than that of the existing clinical targeting drug enzalutamide, among which one of the new compounds is expected to be a candidate drug for the treatment of the castration-resistant prostate cancer.

    [0050] The technical scheme of the present disclosure will be explained in more detail with reference to the following embodiments. Unless otherwise specified, the reagents, equipment, and methods used in the present disclosure are those routinely commercially available and routinely used in the art.

    [0051] In the present disclosure, research was carried out on thymelaeaceae plants (taking daphne genkwa as an example).

    [0052] Equipment and reagents: a Bruker AM-400/500 spectrometer was used for recording NMR spectrum, and a TMS was used as an internal standard. Column chromatography silica gel (300-400 mesh): Qingdao Haiyang Chemical Co., Ltd.; GF.sub.254 silica gel thin-layer chromatography prefabricated plate: Qingdao Haiyang Chemical Co., Ltd.; MCI filler (CHP20P, 75-150 μm): Mitsubishi Chemical Industries Ltd.; Sephadex (Sephadex LH-20): GE Company in USA; ODS filler (12 nm, S-50 μm): YMC. Co., Ltd in Japan; and other solvents and reagents: analytical pure (AR), Baishi Chemical Industry Co., Ltd, Tianjin, China.

    Preparation of Daphnane Diterpenoid Compound

    [0053] Twenty kg of daphne genkwa was taken, and crushed into coarse powder. Three times the volume of 95% ethanol was added, soaked for 1 week, and recovered the ethanol under reduced pressure after suction filtration. The soaking and extraction steps were repeated more than three times, and finally 1500 g of the ethanol extract of daphne genkwa was obtained. The extract of daphne genkwa was dispersed with 1 L of water, and then extracted three times with ethyl acetate. The ethyl acetate extract liquor were combined and concentrated under reduced pressure to obtain 300 g of ethyl acetate extract.

    [0054] The above ethyl acetate extract was taken and loaded on a silica gel column, initially segmented with the mixture of petroleum ether and ethyl acetate, the mixture of dichloromethane and methanol, then further isolated by ODS, MCI, Sephadex LH-20, finally purified by the semi-preparative high-performance liquid chromatography under the conditions of (acetonitrile:water) or (methanol:water), and 34 monomer compounds were obtained. FIG. 1 shows the specific isolation flowchart. The obtained partial daphnane diterpenoid compounds were structurally modified to prepare derivatives thereof

    Identification of Isolated Products

    Example 1

    [0055] Compound YH-30 was obtained by purifying with the semi-preparative HPLC. The structure and data of Compound YH-30 were as follows:

    ##STR00008##

    [0056] YH-30: [α].sup.25.sub.D+7.8 (c 0.230, CH.sub.2Cl.sub.2); UV (MeOH) Amax (log ε) 232 (4.21) nm; ECD (c 3.3×10.sup.−4 M, MeCN) λ.sub.max (Δε) 252 (−2.44) nm; IR (KBr) v.sub.max 3445, 2925, 2856, 1705, 1632, 1451, 1401,1379, 1301, 1268, 1108, 1070,1026, 938, 913, 863 cm.sup.−1; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.55 (1H, s, H-1), 4.20 (1H, s, H-5), 3.61 (1H, s, H-7), 3.59 (1H, d, J=2.4 Hz, H-8), 3.76 (1H, m, H-10), 2.52 (1H, q, J=7.2 Hz, H-11), 5.18 (1H, s, H-12), 4.84 (1H, d, J=2.4 Hz, H-14), 4.99 (2H, s, H-16), 1.84 (3H, s, H.sub.3-17), 1.37 (3H, d, J=7.2 Hz, H.sub.3-18), 1.76 (3H, br s, H.sub.3-19), 3.81 (1H, d, J=12.0 Hz, H-20a), 3.90 (1H, d, J=12.0 Hz, H-20b), 1′-Me: 1.70 (3H, s); 12-OBz: 7.87 (2H, m), 7.44 (2H, m), 7.57 (1H, m); .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 160.3 (C-1), 136.9 (C-2), 209.4 (C-3), 72.2 (C-4), 71.8 (C-5), 60.7 (C-6), 64.1 (C-7), 35.5 (C-8), 77.8 (C-9), 47.4 (C-10), 44.0 (C-11), 78.9 (C-12), 83.9 (C-13), 80.5 (C-14), 143.0 (C-15), 113.5 (C-16), 18.6 (C-17), 18.3 (C-18), 9.8 (C-19), 64.8 (C-20), 118.9 (C-1′), 1′-Me: 21.5, 12-OBz: 165.4, 129.7, 129.4×2, 128.6×2, 133.3; HRESIMS m/z 541.2070 [M+H].sup.+ (calcd for C.sub.29H.sub.33O.sub.10.sup.+, 541.2068).

    Example 2

    [0057] Compound YH-60 was obtained by isolating and purifying with the semi-preparative HPLC. The structure and data of Compound YH-60 were as follows:

    ##STR00009##

    [0058] YH-60: [α].sup.25.sub.D-14.2 (c 0.148, CH.sub.2Cl.sub.2); UV (MeOH) λ.sub.max (log ε) 232 (4.50) nm; IR (KBr) v.sub.max 3418, 2925, 2855, 1704, 1631, 1452, 1379, 1315, 1270, 1178, 1108, 1070, 1026, 1010, 940, 915 cm.sup.−1; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.63 (1H, s, H-1), 4.13 (1H, s, H-5), 3.36 (1H, s, H-7), 4.22 (1H, d, J=5.2 Hz, H-8), 3.51 (1H, s, H-10), 2.51 (1H, m, H-11), 5.22 (1H, d, J=2.2 Hz, H-12), 6.19 (1H, d, J=5.2 Hz, H-14), 5.04 (1H, s, H-16a), 5.34 (1H, s, H-16b), 1.88 (3H, s, H.sub.3-17), 1.40 (3H, d, J=7.3 Hz, H.sub.3-18), 1.75 (3H, br s, H.sub.3-19), 3.34 (1H, d, J=12.3 Hz, H-20a), 4.00 (1H, d, J=12.3 Hz, H-20b), 12-OBz: 7.97 (2H, d, J=7.4 Hz), 7.49 (2H, m), 7.60 (1H, m); 14-OBz: 8.07 (2H, d, J=7.0 Hz), 7.28 (2H, m), 7.60 (1H, m); .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 159.6 (C-1), 137.0 (C-2), 208.6 (C-3), 72.4 (C-4), 69.5 (C-5), 63.1 (C-6), 62.8 (C-7), 40.3 (C-8), 75.8 (C-9), 51.0 (C-10), 42.9 (C-11), 79.9 (C-12), 75.2 (C-13), 73.7 (C-14), 144.5 (C-15), 114.9 (C-16), 19.6 (C-17), 16.2 (C-18), 9.9 (C-19), 65.5 (C-20), 12-OBz: 165.8, 129.4, 129.6×2, 128.6×2, 133.3, 14-OBz:166.6, 129.8, 130.0×2, 128.4×2, 133.4; HRESIMS m/z 619.2168 [M−H].sup.− (calcd for C.sub.34H.sub.35O.sub.11.sup.−, 619.2185).

    Preparation of Derivatives

    [0059] The raw material compounds used in the following examples were YH-6, YH-11, YH-16 and YH-22. The structures of these compounds were as follows:

    ##STR00010##

    Example 3: Preparation of YH-7 and YH-8

    [0060] Compound YH-6 (30 mg) was taken and dissolved in 2 mL of pyridine, and then stirred under the protection of N.sub.2. One-hundred (100) μL of acetic anhydride was pumped into with an injector and heated for reaction at 50° C. Two products were found in thin layer detection. When the raw material was basically reacted, 3 mL of water was added to stop the reaction, and then EtOAc (5 mL) was used to extract three times. After the reaction product was purified with a preparative thin layer (CH.sub.2Cl.sub.2/MeOH, 50:1), YH-7 (10 mg) and YH-8 (15 mg) were obtained. The structure and data were as follows:

    ##STR00011##

    [0061] YH-7: UV (MeOH) λ.sub.max (log) 240 (3.70) nm; .sup.1HNMR (400 MHz, CDCl.sub.3) δ.sub.H 7.72 (2H, m), 7.49 (1H, br s), 7.39 (3H, m), 5.57 (1H, s), 5.05 (2H, s, overlap), 5.02 (1H, s), 4.91 (1H, d, J=2.5 Hz), 4.80 (1H, d, J=12.0 Hz), 4.06 (1H, m), 3.67 (1H, d, J=2.5 Hz), 3.63 (1H, d, J=12.0 Hz), 3.53 (1H, s), 3.07 (1H, s), 2.37 (1H, q, J=7.3 Hz), 2.20 (3H, s), 2.03 (6H, s), 1.88 (3H, s), 1.75 (1H, br s), 1.31 (3H, d, J=7.3 Hz); .sup.13C NMR (100 MHz, CDCl.sub.3) δ.sub.C 10.0, 18.1, 18.8, 20.6, 20.7, 21.1, 35.4, 43.9, 47.9, 59.5, 64.2, 66.3, 68.4, 71.8, 78.1, 78.3, 80.5, 84.1, 113.5, 117.9, 126.0, 128.0, 129.7, 135.1, 137.1, 143.0, 158.2, 168.8, 169.6, 170.6, 205.6; MS m/z 625.2 [M+H].sup.+ 659.2 [M+Cl].sup.−.

    [0062] YH-8: [α].sub.D.sup.25+12.0 (c 0.47, MeOH), UV (MeOH) λ.sub.max (log) 241 (4.16) nm; IR (KBr) v.sub.max 3469, 2929, 1738, 1698, 1234, 1082, and 1024 cm.sup.−1; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.57 (1H, br s, H-1), 4.30 (1H, s, H-5), 3.51 (1H, s, H-7), 3.61 (1H, d, J=2.6 Hz, H-8), 3.96 (1H, m, H-10), 2.46 (1H, q, J=7.3 Hz, H-11), 5.07 (1H, s, H-12), 4.88 (1H, d, J=2.6 Hz, H-14), 5.04 (1H, s, H-16a), 5.02 (1H, s, H-16b), 1.88 (3H, s, H.sub.3-17), 1.35 (3H, d, J=7.3 Hz, H.sub.3-18), 1.78 (3H, brs, H.sub.3-19), 4.83 (1H, d, J=12.0 Hz, H-20a), 3.92 (1H, d, J=12.0 Hz, H-20b). 1′-Ph: 7.71 (2H, m), 7.38 (2H, m), 7.38 (1H, m), 12-OAc: 2.02 (3H. s). 20-OAc: 2.09 (3H, s); .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 160.1 (C-1), 136.9 (C-2), 209.2 (C-3), 72.2 (C-4), 69.8 (C-5), 59.4 (C-6), 64.0 (C-7), 35.3 (C-8), 78.6 (C-9), 47.3 (C-10), 44.0 (C-11), 78.2 (C-12), 84.0 (C-13), 80.7 (C-14), 143.0 (C-15), 113.5 (C-16), 18.8 (C-17), 18.3 (C-18), 9.9 (C-19), 65.7 (C-20), 117.9 (C-1′). 1′-Ph: 135.2, 126.0×2, 128.0×2, 129.6. 12-OAc: 169.6, 21.1. 20-OAc: 170.6, 20.8; HRESIMS m/z 583.2179 [M+H].sup.+ (calcd for C.sub.31H.sub.35O.sub.11.sup.+, 583.2174).

    Example 4: Preparation of Compound YH-9

    [0063] Compound YH-6 (20 mg) was taken and dissolved in 2 mL of dichloromethane. One-hundred (100) L of triethylamine (Et.sub.3N) was added under stirring, and 100 L of benzoyl chloride was added for reaction for 30 min. When the raw material was reacted, 5 mL of H.sub.2O was added to stop the reaction, and then dichloromethane (3×5 mL) was used to extract. The organic phase was concentrated, then purified with a gel (Sephadex LH-20, MeOH) and a preparative thin layer (CH.sub.2Cl.sub.2/MeOH, 50:1), and finally Compound YH-9 (11 mg) was obtained. The structure and data of the compound were as follows:

    ##STR00012##

    [0064] YH-9: [α].sub.D.sup.25+24 (c 0.43, MeOH); UV (MeOH) λ.sub.max (log) 231 (3.50) nm; IR (KBr) v.sub.max 3465, 2925, 1721, 1274, 1240, 1082, and 1023 cm.sup.−1; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.58 (1H, br s, H-1), 4.39 (1H, s, H-5), 3.59 (1H, s, H-7), 3.66 (1H, d, J=2.3 Hz, H-8), 4.01 (1H, br s, H-10), 2.49 (1H, q, J=7.3 Hz, H-11), 5.08 (1H, s, H-12), 4.90 (1H, d, J=2.3 Hz, H-14), 5.03 (1H, s, H-16a), 5.05 (1H, s, H-16b), 1.88 (3H, s, H.sub.3-17), 1.37 (3H, d, J=7.3 Hz, H.sub.3-18), 1.79 (3H, br s, H.sub.3-19), 5.13 (1H, d, J=11.9 Hz, H-20a), 4.10 (1H, d, J=11.9 Hz, H-20b). 1′-Ph: 7.71 (2H, m), 7.38 (2H, m), 7.38 (1H, m). 12-OAc: 2.02 (3H. s). 20-OBz: 8.05 (2H, d, J=7.7 Hz), 7.43 (2H, t, J=7.7 Hz), 7.56 (1H, m); .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 160.1 (C-1), 136.9 (C-2), 209.2 (C-3), 72.3 (C-4), 69.8 (C-5), 59.7 (C-6), 64.2 (C-7), 35.3 (C-8), 78.6 (C-9), 47.3 (C-10), 44.0 (C-11), 78.3 (C-12), 84.1 (C-13), 80.7 (C-14), 143.0 (C-15), 113.5 (C-16), 18.8 (C-17), 18.3 (C-18), 9.9 (C-19), 66.6 (C-20), 117.9 (C-1′). 1′-Ph: 135.2, 126.0×2, 128.0×2, 129.6. 12-OAc: 169.6, 21.1. 20-OBz: 166.2, 129.8, 129.7×2, 128.4×2, 133.2; ESIMS m/z 645.2 [M+H].sup.+, 679.2 [M+Cl].sup.−; HRESIMS m/z 643.2184 [M−H].sup.− (calcd for C.sub.36H.sub.35O.sub.11.sup.−, 643.2185).

    Example 5: Preparation of Compound YH-10

    [0065] Compound YH-6 (20 mg) was taken and dissolved in anhydrous pyridine. Nitrogen was then added for protection after vacuuming, and 100 μL of 2-thiophenecarbonyl chloride was pumped into with an injector and heated for reaction at 50° C. for 2 h. After the completion of the reaction, 5 mL of water was added to quench, and then EtOAc (3×5 mL) was used to extract. The organic phase was concentrated, then purified with a preparative thin layer (CH.sub.2Cl.sub.2/MeOH, 50:1) and a gel (Sephadex LH-20, MeOH), and finally Compound YH-10 (12 mg) was obtained. The structure and data of the compound were as follows:

    ##STR00013##

    [0066] YH-10: Colorless oil: [α].sub.D.sup.25+17.1 (c 0.23, MeOH); UV (MeOH) λ.sub.max (log) 245 (3.94) nm; IR (KBr) v.sub.max 3476, 2924, 1706, 1257, 1230, 1081, and 750 cm.sup.−1; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.57 (1H, br s, H-1), 4.36 (1H, s, H-5), 3.57 (1H, s, H-7), 3.64 (1H, d, J=2.5 Hz, H-8), 3.98 (1H, m, H-10), 2.48 (1H, q, J=7.2 Hz, H-11), 5.07 (1H, s, H-12), 4.90 (1H, d, J=2.5 Hz, H-14), 5.05 (1H, s, H-16a), 5.02 (1H, s, H-16b), 1.88 (3H, s, H.sub.3-17), 1.36 (3H, d, J=7.2 Hz, H.sub.3-18), 1.79 (3H, br s, H.sub.3-19), 5.12 (1H, d, J=11.9 Hz, H-20a), 4.05 (1H, d, J=11.9 Hz, H-20b). 1′-Ph: 7.71 (2H, m), 7.38 (2H, m), 7.38 (1H, m). 12-OAc: 2.02 (3H. s). 2-thenoyl: 7.82 (1H, dd, J=3.7, 1.1 Hz), 7.09 (1H, dd, J=4.8, 3.9 Hz), 7.55 (1H, dd, J=4.8, 1.1 Hz); .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 160.2 (C-1), 137.0 (C-2), 209.2 (C-3), 72.3 (C-4), 69.7 (C-5), 59.7 (C-6), 64.0 (C-7), 35.3 (C-8), 78.6 (C-9), 47.3 (C-10), 44.0 (C-11), 78.2 (C-12), 84.1 (C-13), 80.7 (C-14), 143.0 (C-15), 113.6 (C-16), 18.9 (C-17), 18.3 (C-18), 10.0 (C-19), 66.6 (C-20), 117.9 (C-1′). 1′-Ph: 135.2, 126.0×2, 128.1×2, 129.7. 12-OAc: 169.7, 21.2. 2-thenoyl: 161.8, 133.1, 133.9, 127.9, 132.8; ESIMS m/z 651.2 [M+H].sup.+ [M+Cl].sup.−; HRESIMS m/z 651.1858 (calcd for C.sub.34H.sub.35O.sub.11S.sup.+, 651.1855).

    Example 6: Preparation of Compounds YH-12 and YH-13

    [0067] Compound YH-11 (30 mg) was taken and dissolved in 2 mL of pyridine. Followed by stirring under the protection of N.sub.2, 100 μL of acetic anhydride was pumped into with an injector and heated for reaction at 50° C. Two products were found in thin layer detection. When the raw material was basically reacted, 3 mL of water was added to stop the reaction, and EtOAc (5 mL) was used to extract three times. After the reaction products were purified with a preparative thin layer (CH.sub.2Cl.sub.2/MeOH, 50:1), YH-12 (13 mg) and YH-13 (10 mg) were obtained. The structure and data of the compounds were as follows:

    ##STR00014##

    [0068] YH-12: [α].sup.25+63.3 (c 0.33, MeOH); UV (MeOH) λ.sub.max (log) 231 (3.99) nm; IR (KBr) v.sub.max 3445, 2925, 1710, 1268, 1080, and 713 cm.sup.−1; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.50 (1H, br s, H-1), 5.55 (1H, s, H-5), 3.59 (1H, s, H-7), 3.78 (1H, d, J=2.5 Hz, H-8), 4.08 (1H, m, H-10), 2.55 (1H, q, J=7.2 Hz, H-11), 5.28 (1H, s, H-12), 5.05 (1H, d, J=2.5 Hz, H-14), 5.09 (1H, s, H-16a), 5.04 (1H, s, H-16b), 1.92 (3H, s, H.sub.3-17), 1.40 (3H, d, J=7.2 Hz, H.sub.3-18), 1.74 (3H, br s, H.sub.3-19), 4.79 (1H, d, J=12.0 Hz, H-20a), 3.64 (1H, d, J=12.0 Hz, H-20b). 1′-Ph: 7.75 (2H, m), 7.40 (2H, m), 7.40 (1H, m). 12-OBz: 7.94 (2H, m), 7.48 (2H, m), 7.61 (1H, m). 5-OAc: 2.14 (3H, s). 20-OAc: 2.03 (3H, s); .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 158.0 (C-1), 137.2 (C-2), 205.4 (C-3), 71.7 (C-4), 68.4 (C-5), 59.6 (C-6), 64.2 (C-7), 35.9 (C-8), 78.4 (C-9), 47.9 (C-10), 44.0 (C-11), 78.9 (C-12), 84.3 (C-13), 80.6 (C-14), 142.9 (C-15), 113.8 (C-16), 18.9 (C-17), 18.2 (C-18), 10.0 (C-19), 66.4 (C-20), 118.0 (C-1′). 1′-Ph: 135.1, 126.0×2, 128.1×2, 129.7. 12-OBz: 165.4, 129.7, 129.5×2, 128.6×2, 133.4. 5-OAc: 168.8, 20.7. 20-OAc: 170.6, 20.3; ESIMS m/z 687.3 [M+H].sup.+; HRESIMS m/z 687.2420 [M+H].sup.+ (calcd for C.sub.38H.sub.39O.sub.12.sup.+, 687.2436).

    [0069] YH-13: white powder; [α].sup.25+50.2 (c 0.43, MeOH); UV (MeOH) λ.sub.max (log) 232 (4.02) nm; IR (KBr) v.sub.max 3446, 2925, 1908, 1451, 1365, 1267, 1241, 978, 713 cm.sup.−1; .sup.1HNMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.59 (1H, br s, H-1), 4.28 (1H, d, J=2.4 Hz, H-5), 3.59 (1H, s, H-7), 3.73 (1H, d, J=2.5 Hz, H-8), 3.98 (1H, m, H-10), 2.64 (1H, q, J=7.3 Hz, H-11), 5.32 (1H, s, H-12), 5.01 (1H, d, J=2.5 Hz, H-14), 5.08 (1H, s, H-16a), 5.03 (1H, s, H-16b), 1.92 (3H, s, H.sub.3-17), 1.45 (3H, d, J=7.3 Hz, H.sub.3-18), 1.77 (3H, br s, H.sub.3-19), 4.84 (1H, d, J=12.0 Hz, H-20a), 3.92 (1H, d, J=12.0 Hz, H-20b). 1′-Ph: 7.75 (2H, m), 7.40 (2H, m), 7.40 (1H, m). 12-OBz: 7.92 (2H, m), 7.47 (2H, m), 7.59 (1H, m). 20-OAc: 2.09 (3H, s); .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 160.1 (C-1), 136.9 (C-2), 209.2 (C-3), 72.1 (C-4), 69.8 (C-5), 59.4 (C-6), 64.1 (C-7), 35.7 (C-8), 78.6 (C-9), 47.3 (C-10), 44.1 (C-11), 78.9 (C-12), 84.2 (C-13), 80.7 (C-14), 142.9 (C-15), 113.8 (C-16), 18.9 (C-17), 18.4 (C-18), 9.9 (C-19), 65.8 (C-20), 118.0 (C-1′). 1′-Ph: 135.1, 126.0×2, 128.1×2, 129.7. 12-OBz: 165.4, 129.7, 129.5×2, 128.6×2, 133.4. 20-OAc: 170.6, 20.9; ESIMS m/z 645.3 [M+H].sup.+; HRESIMS m/z 645.2339 [M+H].sup.+ (calcd for C.sub.36H.sub.37O.sub.11.sup.+, 645.2330).

    Example 7: Preparation of Compound YH-25

    [0070] Compound YH-22 (23 mg) was taken, and the product was prepared with reference to the method in Example 4. After the obtained product was purified with a gel (Sephadex LH-20, MeOH) and a preparative thin layer (CH.sub.2Cl.sub.2/MeOH, 100:1), Compound YH-25 (15 mg) was obtained. The structure and data of the compound were as follows:

    ##STR00015##

    [0071] YH-25: Colorless oil; [α].sub.D.sup.25+28.5 (c 0.067, MeOH); UV (MeOH) λ.sub.max (log) 230 (4.50) nm; IR (KBr) v.sub.max 3459, 2926, 1719, 1273, 1230, 1026, and 711 cm.sup.−1; .sup.1HNMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.57 (1H, m, H-1), 4.37 (1H, s, H-5), 3.52 (1H, s, H-7), 3.57 (1H, d, J=2.5 Hz, H-8), 3.91 (1H, m, H-10), 2.40 (1H, q, J=7.2 Hz, H-11), 4.99 (1H, s, H-12), 4.76 (1H, d, J=2.5 Hz, H-14), 5.01 (1H, s, H-16a), 4.97 (1H, s, H-16b), 1.84 (3H, s, H.sub.3-17), 1.30 (3H, d, J=7.2 Hz, H-18), 1.78 (3H, br s, H.sub.3-19), 5.12 (1H, d, J=11.9 Hz, H-20a), 4.07 (1H, d, J=11.9 Hz, H-20b), 5.64 (1H, d, J=15.5 Hz, H-2′), 6.66 (1H, dd, J=15.5, 10.6 Hz, H-3′), 6.03 (1H, dd, J=15.0, 10.6 Hz, H-4′), 5.85 (1H, dd, J=15.0, 7.4 Hz, H-5′), 2.08 (2H, m, H.sub.2-6′), 1.37 (2H, m, H.sub.2-7′), 1.26 (2H, m, H.sub.2-8′), 1.26 (2H, m, H.sub.2-9′), 0.87 (3H, t, J=6.9 Hz, H-10′). 12-OAc: 1.99 (3H. s). 20-OBz: 8.04 (2H, d, J=7.3 Hz), 7.44 (2H, m), 7.56 (1H, m); .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 160.2 (C-1), 136.9 (C-2), 209.2 (C-3), 72.3 (C-4), 69.7 (C-5), 59.7 (C-6), 64.1 (C-7), 35.2 (C-8), 78.1 (C-9), 47.3 (C-10), 43.9 (C-11), 78.2 (C-12), 83.6 (C-13), 80.3 (C-14), 143.1 (C-15), 113.3 (C-16), 18.7 (C-17), 18.2 (C-18), 9.9 (C-19), 66.6 (C-20), 117.1 (C-1′), 122.2 (C-2′), 135.0 (C-3′), 128.5 (C-4′), 139.3 (C-5′), 32.6 (C-6′), 28.7 (C-7′), 31.3 (C-8′), 22.5 (C-9′), 14.0 (C-10′). 12-OAc: 169.7, 21.1. 20-OBz: 166.2, 129.7, 129.7×2, 128.4×2, 133.1; ESIMS m/z 691.3 [M+H].sup.+, 725.2 [M+Cl].sup.−; HRESIMS m/z 689.2962 [M−H].sup.− (calcd for C.sub.39H.sub.45O.sub.11, 689.2967).

    Example 8: Preparation of Compound YH-33

    [0072] Compound YH-22 (30 mg) was taken and dissolved in dichloromethane. Ten (10) mg of Grubbs second-generation catalyst was then added, and nitrogen was added for protection after vacuuming. Two hundred (200) μL of styrene was pumped into with an injector, and then heated for reaction under stirring at 40° C. for 1 h. The catalyst was removed by filtration, the filtrate was concentrated and then purified with an HPLC (MeCN/H.sub.2O, 75%, 3 mL/min), and finally Compound YH-33 (15 mg, t.sub.R=10 min) was obtained. The structure and data of the compound were as follows:

    ##STR00016##

    [0073] YH-33: [α].sub.D.sup.25+4.2 (c 0.33, MeOH); UV (MeOH) λ.sub.max (log) 286 (4.26) nm; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.59 (1H, br s, H-1), 4.27 (1H, s, H-5), 3.57 (1H, s, H-7), 3.53 (1H, d, J=2.5 Hz, H-8), 3.85 (1H, m, H-10), 2.39 (1H, q, J=7.3 Hz, H-11), 5.00 (1H, s, H-12), 4.79 (1H, d, J=2.5 Hz, H-14), 5.03 (1H, br s, H-16a), 4.97 (1H, br s, H-16b), 1.85 (3H, s, H.sub.3-17), 1.31 (3H, d, J=7.3 Hz, H.sub.3-18), 1.80 (3H, br s, H.sub.3-19), 3.94 (1H, d, J=12.4 Hz, H-20a), 3.81 (1H, d, J=12.4 Hz, H-20b), 5.88 (1H, d, J=14.9 Hz, H-2′), 6.86 (1H, dd, J=14.9, 10.0 Hz, H-3′), 6.77 (1H, dd, J=15.1, 10.0 Hz, H-4′), 6.69 (1H, d, J=15.1 Hz, H-5′), 7.40 (2H, m, H-7′/H-11′), 7.32 (1H, dd, J=7.5, 7.5 Hz, H-8′/H-10′), 7.26 (1H, m, H-9′); 12-OAc: 2.00 (3H, s); .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 160.3 (C-1), 136.9 (C-2), 209.4 (C-3), 72.2 (C-4), 71.9 (C-5), 60.5 (C-6), 64.2 (C-7), 35.4 (C-8), 78.3 (C-9), 47.4 (C-10), 44.0 (C-11), 78.2 (C-12), 83.8 (C-13), 80.5 (C-14), 143.0 (C-15), 113.4 (C-16), 18.7 (C-17), 18.3 (C-18), 9.9 (C-19), 65.1 (C-20), 116.8 (C-1′), 124.9 (C-2′), 134.8 (C-3′), 127.0 (C-4′), 136.0 (C-5′), 136.7 (C-6′), 126.7 (C-7′/C-11′), 128.6 (C-8′/10′), 128.1 (C-9′), 12-OAc: 169.7, 21.2; HRESIMS m/z 615.2206 [M+Na].sup.+ (calcd for, C.sub.33H.sub.36O.sub.10Na+, 615.2201) and 627.1993 [M+Cl].sup.− (calcd for C.sub.33H.sub.36O.sub.10Cl.sup.−, 627.2002).

    Example 9: Preparation of Compound YH-34

    [0074] Compound YH-16 (30 mg) was taken, and the product was prepared with reference to the method in Example 8. After the obtained product was purified with an HPLC (MeCN/H.sub.2O, 80%, 3 mL/min), Compound YH-34 (16 mg, t.sub.R=14 min) was obtained. The structure and data of the compound were as follows:

    ##STR00017##

    [0075] YH-34: [α].sup.25+27.8 (c 0.13, MeOH); UV (MeOH) λ.sub.max (log) 285 (4.24) nm; .sup.1H NMR (CDCl.sub.3, 500 MHz) δ.sub.H 7.61 (1H, br s, H-1), 4.23 (1H, s, H-5), 3.66 (1H, s, H-7), 3.65 (1H, d, J=2.7 Hz, H-8), 3.87 (1H, m, H-10), 2.58 (1H, q, J=7.2 Hz, H-11), 5.24 (1H, s, H-12), 4.93 (1H, d, J=2.7 Hz, H-14), 5.04 (1H, br s, H-16a), 5.02 (1H, br s, H-16b), 1.89 (3H, s, H.sub.3-17), 1.41 (3H, d, J=7.2 Hz, H.sub.3-18), 1.79 (3H, br s, H.sub.3-19), 3.94 (1H, d, J=12.2 Hz, H-20a), 3.83 (1H, d, J=12.2 Hz, H-20b), 5.91 (1H, d, J=15.2 Hz, H-2′), 6.90 (1H, dd, J=15.2, 10.5 Hz, H-3′), 6.78 (1H, dd, J=15.4, 10.5 Hz, H-4′), 6.73 (1H, d, J=15.4 Hz, H-5′), 7.41 (2H, d, J=7.6 Hz, H-7′/H-11′), 7.33 (1H, dd, J=7.6, 7.6 Hz, H-8′/H-10′), 7.26 (1H, m, H-9′); 12-OBz: 7.90 (2H, d, J=7.6 Hz), 7.46 (2H, dd, J=7.6, 7.6 Hz), 7.58 (1H, dd, J=7.6, 7.6 Hz); .sup.13C NMR (CDCl.sub.3, 125 MHz) δ.sub.C 160.2 (C-1), 137.0 (C-2), 209.3 (C-3), 72.2 (C-4), 71.8 (C-5), 60.6 (C-6), 64.0 (C-7), 35.8 (C-8), 78.4 (C-9), 47.4 (C-10), 44.1 (C-11), 78.9 (C-12), 84.0 (C-13), 80.5 (C-14), 142.9 (C-15), 113.7 (C-16), 18.8 (C-17), 18.3 (C-18), 9.9 (C-19), 64.7 (C-20), 116.9 (C-1′), 124.8 (C-2′), 134.8 (C-3′), 127.0 (C-4′), 136.1 (C-5′), 136.7 (C-6′), 126.7 (C-7′/C-11′), 128.6 (C-8′/10′), 128.1 (C-9′), 12-OBz: 129.6, 129.5×2, 128.7×2, 133.3; HRESIMS m/z 689.2147 [M+Cl].sup.− (calcd for C.sub.38H.sub.38O.sub.10Cl.sup.−, 689.2159).

    Example 10: Preparation of Compound YH-37

    [0076] Compound YH-22 (20 mg) was taken and dissolved in 3 mL of methanol. Twenty (20) mg of palladium-carbon catalyst was then added, and hydrogen was added for protection after vacuuming. Followed by stirring for reaction at a room temperature for 30 min, the palladium-carbon was removed by filtration. The filtrate was concentrated, then purified directly with an HPLC (MeCN/H.sub.2O, 95%, 3 mL/min), and finally Compound YH-37 (12 mg, t.sub.R=14 min) was obtained. The structure and data of the compound were as follows:

    ##STR00018##

    [0077] YH-37: [α].sup.25+87.0 (c 0.033, MeOH); UV (MeOH) λ.sub.max (log) 243 (4.03) nm; IR (KBr) v.sub.max 3465, 2925, 1744, 1698, 1230, 1027, and 936 cm.sup.−1; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.53 (1H, br s, H-1), 4.23 (1H, s, H-5), 3.49 (1H, s, H-7), 3.34 (1H, d, J=2.4 Hz, H-8), 3.73 (1H, m, H-10), 2.30 (1H, q, J=7.3 Hz, H-11), 4.93 (1H, s, H-12), 4.44 (1H, d, J=2.4 Hz, H-14), 1.85 (1H, m, H-15), 0.91 (3H, d, J=6.9 Hz, H.sub.3-16), 0.93 (3H, d, J=6.9 Hz, H.sub.3-17), 1.22 (3H, d, J=7.3 Hz, H.sub.3-18), 1.78 (3H, br s, H.sub.3-19), 3.89 (1H, d, J=12.4 Hz, H-20a), 3.79 (1H, d, J=12.4 Hz, H-20b), 1.87 (2H, m, H.sub.2-2′), 1.54 (2H, m, H.sub.2-3′), 1.27-1.30 (8H, m, H-4′-H-7′), 1.30 (2H, m, H.sub.2-8′), 1.26 (2H, m, H.sub.2-9′), 0.87 (3H, t, J=6.8 Hz, H-10′); 12-OAc: 2.00 (3H, s); .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 160.9 (C-1), 136.6 (C-2), 209.7 (C-3), 72.2 (C-4), 72.0 (C-5), 60.4 (C-6), 64.5 (C-7), 35.5 (C-8), 77.2 (C-9), 47.5 (C-10), 44.0 (C-11), 77.5 (C-12), 83.6 (C-13), 80.0 (C-14), 31.3 (C-15), 16.6 (C-16), 15.9 (C-17), 18.1 (C-18), 9.8 (C-19), 65.2 (C-20), 119.9 (C-1′), 34.8 (C-2′), 23.4 (C-3′), 29.6 (C-4′), 29.5 (C-5′), 29.5 (C-6′), 29.3 (C-7′), 22.7 (C-8′), 31.8 (C-9′), 14.1 (C-10′); 12-OAc: 169.9, 21.2; HRESIMS m/z 593.3315 [M+H].sup.+ (calcd for C.sub.32H.sub.49O.sub.10.sup.+, 593.3320).

    Example 11: Preparation of Compound YH-38

    [0078] Compound YH-22 (20 mg) was taken and dissolved in 3 mL of methanol. Thirty (30) mg of palladium-carbon catalyst was then added, and hydrogen was added for protection after vacuuming. Followed by stirring for reaction at 50° C. for 30 min, the palladium-carbon was removed by filtration. The filtrate was concentrated, and then purified with an HPLC (MeCN/H.sub.2O, 95%, 3 mL/min), and finally Compound YH-38 (9 mg, t.sub.R=15 min) was obtained. The structure and data of the compound were as follows:

    ##STR00019##

    [0079] YH-38: [α].sup.25+76.8 (c 0.67, MeOH); UV (MeOH) λ.sub.max (log) 202 (3.50) nm; IR (KBr) v.sub.max 3463, 2927, 1742, 1378, 1229, 1028, and 940 cm.sup.−1; .sup.1H NMR (CDCl.sub.3, 500 MHz) δ111.53 (1H, m, H-la), 2.28 (1H, m, H-1b) 2.28 (1H, m, H-2), 4.07 (1H, s, H-5), 3.44 (1H, s, H-7), 3.32 (1H, s, H-8), 2.84 (1H, m, H-10), 2.25 (1H, m, H-11), 5.03 (1H, s, H-12), 4.40 (1H, s, H-14), 1.83 (1H, m, H-15), 0.93 (3H, d, J=6.7 Hz, H.sub.3-16), 0.93 (3H, d, J=6.7 Hz, H.sub.3-17), 1.25 (3H, d, J=7.3 Hz, H.sub.3-18), 1.10 (3H, d, J=5.5 Hz, H.sub.3-19), 3.87 (1H, d, J=12.2 Hz, H-20a), 3.75 (1H, d, J=12.2 Hz, H-20b), 1.84 (2H, m, H.sub.2-2′), 1.52 (2H, m, H.sub.2-3′), 1.25-1.31 (8H, m, H-4′-H-7′), 1.28 (2H, m, H.sub.2-8′), 1.26 (2H, m, H.sub.2-9′), 0.87 (3H, t, J=6.7 Hz, H-10′); 12-OAc: 2.00 (3H, s); .sup.13C NMR (CDCl.sub.3, 125 MHz) δ.sub.C 33.3 (C-1), 42.8 (C-2), 220.3 (C-3), 75.0 (C-4), 71.1 (C-5), 60.7 (C-6), 64.5 (C-7), 35.5 (C-8), 77.6 (C-9), 44.0 (C-10), 43.5 (C-11), 76.8 (C-12), 83.1 (C-13), 80.3 (C-14), 31.2 (C-15), 16.5 (C-16), 15.9 (C-17), 18.3 (C-18), 12.4 (C-19), 65.4 (C-20), 120.0 (C-1′), 34.9 (C-2′), 23.3 (C-3′), 29.6 (C-4′), 29.5 (C-5′), 29.5 (C-6′), 29.3 (C-7′), 22.6 (C-8′), 31.8 (C-9′), 14.1 (C-10′); 12-OAc: 170.0, 21.2; HRESIMS m/z 617.3316 [M+Na].sup.+ (calcd for C.sub.32H.sub.50O.sub.10.sup.+, 617.3296).

    Example 12: Preparation of Compound YH-39

    [0080] Compound YH-11 was taken, and the product was prepared with reference to the method in Example 11. After the obtained product was purified with an HPLC (MeCN/H.sub.2O, 70%, 3 mL/min), Compound YH-39 (10 mg, t.sub.R=17 min) was obtained. The structure and data of the compound were as follows:

    ##STR00020##

    [0081] YH-39: [α].sup.25+64.5 (c 0.067, MeOH); UV (MeOH) λ.sub.max (log) 230 (4.08) nm; IR (KBr) v.sub.max 3483, 2968, 1720, 1272, 1079, and 1025 cm.sup.−1; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ112.36 (1H, m, H-1α), 1.61 (1H, m, H-1β), 2.25 (1H, m, H-2), 4.05 (1H, s, H-5), 3.62 (1H, s, H-7), 3.59 (1H, d, J=2.4 Hz, H-8), 3.01 (1H, dd, J=13.2, 5.8 Hz, H-10), 2.54 (1H, q, J=6.9 Hz, H-11), 5.42 (1H, s, H-12), 4.74 (1H, d, J=2.4 Hz, H-14), 2.03 (1H, m, H-15), 1.04 (3H, d, J=6.7 Hz, H.sub.3-16), 1.04 (3H, d, J=6.7 Hz, H.sub.3-17), 1.46 (3H, d, J=6.9 Hz, H.sub.3-18), 1.09 (3H, d, J=6.6 Hz, H.sub.3-19), 3.86 (1H, d, J=12.3 Hz, H-20a), 3.79 (1H, d, J=12.3 Hz, H-20b); 1′-Ph: 7.75 (2H, m), 7.39 (2H, m), 7.39 (1H, m). 12-OBz: 7.94 (2H, d, J=7.4 Hz), 7.47 (2H, dd, J=7.4, 7.4 Hz), 7.59 (1H, dd, J=7.4, 7.4 Hz); .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 33.4 (C-1), 42.8 (C-2), 220.1 (C-3), 74.9 (C-4), 71.2 (C-5), 60.7 (C-6), 64.4 (C-7), 36.1 (C-8), 78.9 (C-9), 44.1 (C-10), 43.8 (C-11), 77.3 (C-12), 84.1 (C-13), 81.0 (C-14), 31.6 (C-15), 16.7 (C-16), 16.2 (C-17), 18.6 (C-18), 12.4 (C-19), 65.1 (C-20), 118.1 (C-1′). 1′-Ph: 135.7, 125.9×2, 128.0×2, 129.5. 12-OBz: 165.6, 129.8, 129.5×2, 128.6×2, 133.3; HRESIMS m/z 605.2407 [M−H](calcd for C.sub.34H.sub.37O.sub.10.sup.−, 605.2392).

    Example 13: Preparation of Compound YH-47 and Compound YH-48

    [0082] Compound YH-6 (30 mg) was taken and dissolved in 2 mL of tetrahydrofuran (THF). Two-hundred (200) μL of concentrated hydrochloric acid was added for reaction for about 20 min under stirring, 10 mL of water was added to stop the reaction, and then EtOAc (3×10 mL) was added for extraction. After the reaction products passed through a gel (MeOH) and a preparative thin layer (CH.sub.2Cl.sub.2/MeOH, 40:1), Compound YH-47 (13 mg) and Compound YH-48 (10 mg) were obtained. The structure and data of the compounds were as follows:

    ##STR00021##

    [0083] YH-47:[α].sub.D.sup.25+10.5 (c 0.13,MeOH); UV (MeOH) λ.sub.max (log) 241 (3.70) nm; IR (KBr) v.sub.max 3451, 2925, 1740, 1691, 1230, 1078, and 697 cm.sup.−1; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.61 (1H, br s, H-1), 4.38 (1H, s, H-5), 4.74 (1H, s, H-7), 3.60 (1H, d, J=2.4 Hz, H-8), 4.04 (1H, m, H-10), 2.85 (1H, q, J=7.3 Hz, H-11), 5.03 (1H, s, H-12), 4.96 (1H, d, J=2.4 Hz, H-14), 5.03 (1H, s, H-16a), 5.06 (1H, s, H-16b), 1.87 (3H, s, H.sub.3-17), 1.35 (3H, d, J=7.3 Hz, H.sub.3-18), 1.81 (3H, br s, H.sub.3-19), 4.01 (1H, d, J=11.3 Hz, H-20a), 4.16 (1H, d, J=11.3 Hz, H-20b). 1′-Ph: 7.64 (2H, m), 7.41 (2H, m), 7.40 (1H, m). 12-OAc: 1.98 (3H. s); .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 158.6 (C-1), 136.7 (C-2), 208.6 (C-3), 75.2 (C-4), 70.9 (C-5), 76.9 (C-6), 81.4 (C-7), 36.2 (C-8), 78.9 (C-9), 49.9 (C-10), 43.5 (C-11), 77.7 (C-12), 84.7 (C-13), 82.7 (C-14), 142.4 (C-15), 113.9 (C-16), 18.7 (C-17), 17.8 (C-18), 9.9 (C-19), 68.8 (C-20), 117.7 (C-1′). 1′-Ph: 134.6, 125.8×2, 128.2×2, 130.0. 12-OAc: 169.5, 20.9; HRESIMS m/z 575.1685 [M−H](calcd. for C.sub.29H.sub.32O.sub.10Cl.sup.−, 575.1689).

    [0084] YH-48:[α].sub.D.sup.25+15 (c 0.1, MeOH); UV (MeOH) λ.sub.max (log) 241 (3.70) nm; IR (KBr) v.sub.max 3451, 2925, 1740, 1691, 1230, 1078, and 697 cm.sup.−1; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.59 (1H, br s, H-1), 3.96 (1H, s, H-5), 4.89 (1H, d, J=9.8 Hz, H-7), 3.06 (1H, m, H-8), 3.07 (1H, m, H-10), 2.85 (1H, q, J=7.2 Hz, H-11), 5.02 (1H, s, H-12), 5.37 (1H, d, J=2.4 Hz, H-14), 5.01 (1H, s, H-16a), 5.03 (1H, s, H-16b), 1.85 (3H, s, H.sub.3-17), 1.33 (3H, d, J=7.2 Hz, H.sub.3-18), 1.80 (3H, br s, H.sub.3-19), 4.06 (1H, d, J=10.4 Hz, H-20a), 4.46 (1H, d, J=10.4 Hz, H-20b). 1′-Ph: 7.67 (2H, m), 7.39 (2H, m), 7.39 (1H, m). 12-OAc: 2.03 (3H. s); .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 158.9 (C-1), 137.6 (C-2), 208.5 (C-3), 73.3 (C-4), 81.7 (C-5), 79.0 (C-6), 66.9 (C-7), 36.8 (C-8), 78.4 (C-9), 50.6 (C-10), 42.8 (C-11), 77.9 (C-12), 84.2 (C-13), 79.1 (C-14), 142.8 (C-15), 113.7 (C-16), 18.8 (C-17), 18.1 (C-18), 10.0 (C-19), 61.8 (C-20), 117.4 (C-1′). 1′-Ph: 134.8, 125.9×2, 128.1×2, 129.8. 12-OAc: 169.7, 21.0; HRESIMS m/z 575.1681 [M−H].sup.− (calcd. for C.sub.29H.sub.32O.sub.10Cl.sup.−, 575.1689).

    Example 14: Preparation of Compound YH-49 and Compound YH-50

    [0085] Compound YH-11 (40 mg) was taken, and the product was prepared by using the same method in Example 13. After purifying the obtained product with a preparative thin layer (CH.sub.2Cl.sub.2/MeOH, 50:1), Compound YH-49 (20 mg) and Compound YH-50 (12 mg) were obtained. The structure and data of the compounds were as follows:

    ##STR00022##

    [0086] YH-49:[α].sub.D.sup.25+23.6 (c 0.46,MeOH); UV (MeOH) λ.sub.max (log) 231 (4.01) nm; IR (KBr) v.sub.max 3450, 2924, 1721, 1268, 1079, and 711 cm.sup.−1; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.64 (1H, s, H-1), 4.40 (1H, s, H-5), 4.84 (1H, s, H-7), 3.79 (1H, d, J=2.4 Hz, H-8), 4.08 (1H, m, H-10), 2.99 (1H, q, J=7.3 Hz, H-11), 5.34 (1H, s, H-12), 5.10 (1H, d, J=2.4 Hz, H-14), 5.07 (1H, s, H-16a), 5.03 (1H, s, H-16b), 1.91 (3H, s, H.sub.3-17), 1.45 (3H, d, J=7.3 Hz, H.sub.3-18), 1.81 (3H, br s, H.sub.3-19), 4.16 (1H, d, J=11.5 Hz, H-20a), 4.02 (1H, d, J=11.5 Hz, H-20b). 1′-Ph: 7.68 (2H, m), 7.42 (2H, m), 7.44 (1H, m). 12-OBz: 7.97 (2H, m), 7.42 (2H, m), 7.55 (1H, t, J=7.4 Hz); .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 158.6 (C-1), 136.9 (C-2), 208.6 (C-3), 75.1 (C-4), 70.9 (C-5), 77.0 (C-6), 81.6 (C-7), 36.6 (C-8), 79.1 (C-9), 49.9 (C-10), 43.8 (C-11), 78.0 (C-12), 85.1 (C-13), 82.9 (C-14), 142.4 (C-15), 114.2 (C-16), 18.8 (C-17), 18.0 (C-18), 9.9 (C-19), 68.9 (C-20), 117.9 (C-1′). 1′-Ph: 134.6, 125.8×2, 128.3×2, 130.1. 12-OBz: 165.1, 129.4, 129.6×2, 128.4×2, 133.4; HRESIMS m/z 637.18513 [M−H].sup.− (calcd for C.sub.34H.sub.34O.sub.10Cl.sup.−, 637.18460).

    [0087] YH-50: [α].sub.D.sup.25+16.7 (c 0.35, MeOH); UV (MeOH) λ.sub.max (log) 230 (4.10) nm; IR (KBr) v.sub.max 3431, 2960, 1721, 1451, 1268, and 1075 cm.sup.−1; .sup.1H NMR (CDCl.sub.3, 500 MHz) δ.sub.H 7.62 (1H, br s, H-1), 3.90 (1H, s, H-5), 4.90 (1H, d, J=9.9 Hz, H-7), 3.12 (1H, d, J=9.9 Hz, H-8), 3.06 (1H, br s, H-10), 2.99 (1H, q, J=7.2 Hz, H-11), 5.28 (1H, s, H-12), 5.51 (1H, s, H-14), 5.06 (1H, s, H-16a), 5.01 (1H, s, H-16b), 1.88 (3H, s, H.sub.3-17), 1.44 (3H, d, J=7.2 Hz, H-18), 1.78 (3H, br s, H-19), 4.33 (1H, d, J=11.1 Hz, H-20a), 4.06 (1H, d, J=11.1 Hz, H-20b). 1′-Ph: 7.71 (2H, d, J=7.3 Hz), 7.42 (2H, m), 7.43 (1H, m). 12-OBz: 7.94 (2H, d, 7.4), 7.47 (2H, m), 7.59 (1H, t, J=7.4 Hz); .sup.13C NMR (CDCl.sub.3, 125 MHz) δ.sub.C 158.9 (C-1), 137.6 (C-2), 208.4 (C-3), 73.1 (C-4), 81.8 (C-5), 78.5 (C-6), 66.5 (C-7), 37.1 (C-8), 78.4 (C-9), 50.4 (C-10), 43.0 (C-11), 78.5 (C-12), 84.4 (C-13), 79.2 (C-14), 142.8 (C-15), 114.0 (C-16), 18.9 (C-17), 18.3 (C-18), 10.0 (C-19), 62.1 (C-20), 117.5 (C-1′). 1′-Ph: 134.8, 125.9×2, 128.2×2, 130.1. 12-OBz: 165.0, 129.4, 129.4×2, 128.7×2, 133.6; HRESIMS m/z 637.18536 [M−H].sup.− (calcd for C.sub.34H.sub.34O.sub.10Cl.sup.−, 637.18460).

    Example 15: Preparation of Compound YH-52 and Compound YH-53

    [0088] Compound YH-11 (100 mg) was taken and dissolved in 3 mL of dichloromethane, then stirred at −60° C. for 5 minutes, and PBr.sub.3 (50 μL) was added. After the thin layer detects the end of the reaction, the reaction solution was taken out and then quenched by the addition of 5 mL of water. Followed by adding dichloromethane for extraction (3×5 mL), the organic layer was combined, concentrated under a reduced pressure, then purified with a semi-preparative high-performance liquid phase (MeCN/H.sub.2O, 80: 20, 3 mL/min), and finally Compound YH-52 (23 mg, t.sub.R=15 min) and Compound YH-53 (20 mg, t.sub.R=12 min) were obtained. The structure and data of the compounds were as follows:

    ##STR00023##

    [0089] YH-52: [α].sub.D.sup.25+56.3 (c 0.35, MeOH); UV (MeOH) λ.sub.max (log) 232 (3.96) nm; IR (KBr) v.sub.max 3445, 2923, 1720, 1692, 1268, 1078, 1008, and 710 cm.sup.−1; .sup.1H NMR (CDCl.sub.3, 400 MHz) δ.sub.H 7.64 (1H, s, H-1), 4.27 (1H, s, H-5), 4.98 (1H, s, H-7), 3.88 (1H, d, J=2.4 Hz, H-8), 4.08 (1H, s, H-10), 3.00 (1H, q, J=7.3 Hz, H-11), 5.33 (1H, s, H-12), 5.11 (1H, d, J=2.4 Hz, H-14), 5.04 (1H, s, H-16a), 5.08 (1H, s, H-16b), 1.91 (3H, s, H.sub.3-17), 1.45 (3H, d, J=7.3 Hz, H.sub.3-18), 1.81 (3H, br s, H.sub.3-19), 4.10 (1H, d, J=12.0 Hz, H-20a), 4.21 (1H, m, H-20b), 12-OBz: 8.01 (2H, m), 7.39 (2H, m), 7.55 (1H, m); 1′-Ph: 7.68 (2H, m), 7.44 (3H, m); .sup.13C NMR (CDCl.sub.3, 100 MHz) δ.sub.C 158.6 (C-1), 136.9 (C-2), 208.7 (C-3), 75.1 (C-4), 70.5 (C-5), 75.8 (C-6), 82.5 (C-7), 37.8 (C-8), 79.2 (C-9), 50.0 (C-10), 43.8 (C-11), 78.1 (C-12), 85.1 (C-13), 82.8 (C-14), 142.4 (C-15), 114.2 (C-16), 18.8 (C-17), 18.0 (C-18), 9.9 (C-19), 69.9 (C-20), 117.9 (C-1′), 1′-Ph: 134.5, 125.8×2, 128.4×2, 130.1, 12-OBz: 165.1, 129.3, 129.8×2, 128.3×2, 133.4; HRESIMS m/z 705.1309 [M+Na].sup.+ (calcd for, C.sub.34H.sub.35O.sub.10BrNa.sup.+, 705.1306).

    [0090] YH-53: [α].sup.25+50.0 (c 0.30, MeOH); UV (MeOH) λ.sub.max (log) 232 (4.06) nm; IR (KBr) v.sub.max 3428, 1701, 1452, 1268, 1079, 1026, and 712 cm.sup.−1; .sup.1H NMR (CDCl.sub.3, 500 MHz) δ.sub.H 7.57 (1H, s, H-1), 3.85 (1H, s, H-5), 5.06 (1H, d, J=9.9 Hz, H-7), 3.12 (1H, d, J=9.9 Hz, H-8), 3.07 (1H, br s, H-10), 3.00 (1H, q, J=7.2 Hz, H-11), 5.28 (1H, s, H-12), 5.57 (1H, d, J=1.3 Hz, H-14), 5.00 (1H, s, H-16a), 5.04 (1H, s, H-16b), 1.88 (3H, s, H.sub.3-17), 1.42 (3H, d, J=7.2 Hz, H.sub.3-18), 1.73 (3H, br s, H.sub.3-19), 4.09 (1H, d, J=10.9 Hz, H-20a), 4.39 (1H, d, J=10.9 Hz, H-20b), 12-OBz: 7.93 (2H, d, J=7.5 Hz), 7.46 (2H, dd, J=7.5, 7.5 Hz), 7.56 (1H, m); 1′-Ph: 7.71 (2H, m), 7.42 (2H, m), 7.41 (1H, m); .sup.13C NMR (CDCl.sub.3, 125 MHz) δ.sub.C 158.8 (C-1), 137.5 (C-2), 208.2 (C-3), 73.4 (C-4), 81.1 (C-5), 78.2 (C-6), 63.7 (C-7), 36.9 (C-8), 78.5 (C-9), 50.7 (C-10), 43.0 (C-11), 78.4 (C-12), 84.7 (C-13), 81.8 (C-14), 142.7 (C-15), 114.0 (C-16), 18.9 (C-17), 18.2 (C-18), 9.9 (C-19), 63.6 (C-20), 117.3 (C-1′), 1′-Ph: 134.9, 125.9×2, 128.1×2, 129.8, 12-OBz: 165.0, 129.4, 129.4×2, 128.7×2, 133.6; HRESIMS m/z 705.1289 [M+Na].sup.+ (calcd for, C.sub.34H.sub.35O.sub.10BrNa.sup.+, 705.1306).

    Inhibitory Activity of Daphnane Diterpenoid Compound on Castration-Resistant Prostate Cancer Cells

    (1) Cells Culture

    [0091] All prostate cancer cells were cultured with a RPMI-1640 medium containing 10% calf serum, 100 units of penicillin per milliliter and 100 g/mL of streptomycin in a constant temperature incubator containing 5% carbon dioxide at a saturated humidity of 37° C.

    (2) Cytotoxic Activity Test

    [0092] Cells in the logarithmic phase of growth were taken and cultured in 96-well plates for 24 hours (5×10.sup.3 cells/well), then treated with different concentrations of the compounds to be tested, and incubated by MTT method for 4 hours. The supernatant was removed by centrifugation, the MTT crystals were dissolved by adding DMSO, and the absorbance value was measured by an enzyme-linked immunosorbent assay at a wavelength of 570 nm. The cytotoxic activity of the compounds to be tested on cancer cells was expressed as IC.sub.50.

    (3) Experimental Results

    [0093] As shown in Table 1, most of the daphnane diterpenoids showed different degrees of activity in inhibiting a variety of prostate cancer cells. Some representative compounds had a significant inhibitory activity on prostate cancer cells, with an IC.sub.50 at an nM level, which were stronger than that of the positive drugs doxorubicin and enzalutamide (ENZ), among which the activity of the compounds YH-11, YH-22 and YH-52 were the most prominent. A preliminary structure-activity relationship analysis showed that the inhibitory activity of the compounds that contain 9,13,14-orthoesters (YH-11 and YH-52, etc.) was significantly higher than that of compounds without orthoesters (YH-56, YH-60 and YH-61), which indicated that the orthoester was the key pharmacophore. Next, the substitution of 20-OH by an ester-philic groups may lead to a significant decrease in activity, such as the activity of the compounds YH-5, YH-9, YH-12, YH-19, YH-20, YH-25, etc. Additionally, the 6,7-epoxy had a significantly reduced activity when being ring-opened to form a dihydroxy product YH-51, and had an enhanced activity and a significantly reduced toxicity for the normal human prostate cell RWPE-1 than that of prototype compound YH-11 when being ring-opened to form a bromination product YH-52. Such compounds having modifications to the 1′-olefin side chain had unforeseen effects on activity, but overall, compounds with 1′-olefin side chains were more cytotoxic, for example, the compounds YH-16 and YH-22 were more cytotoxic than compounds YH-11 and YH-6. Compounds YH-52 was selected as a candidate for in vivo pharmacodynamic evaluation in animals.

    TABLE-US-00005 TABLE 1 inhibitory activity of representative daphnane diterpenoids compounds on several human prostate cancer cells and normal cells Prostate cancer cells IC.sub.50 (μM) Normal cells No. C4-2B C4-2B/ENZR LNcap Vcap-CRPC 22RV1 RWPE-1 YH-1 3.41 × e.sup.−6 1.56 × e.sup.−4 3.76 × e.sup.−5 1.41 × e.sup.−5 0.00574 43.5 YH-2 8.21 × e.sup.−5 3.36 × e.sup.−5 4.25 × e.sup.−5 1.17 × e.sup.−5 0.0265 40.3 YH-3 0.00895 4.03 × e.sup.−4 0.00377 0.00174 0.434 57.2 YH-5 0.904 0.434 0.0993 4.66 44.5 72.8 YH-6 0.000367 0.00234 0.00389 0.0212 0.0525 44.2 YH-9 0.380 1.462 NA NA NA NA YH-11 8.14 × e.sup.−7 2.46 × e.sup.−7 3.31 × e.sup.−7 2.93 × e.sup.−7 1.36 × e.sup.−4 13.4 YH-12 0.557 1.90 NA NA NA NA YH-13 7.10 × e.sup.−3 0.00679 0.00453 0.0672 0.0832 35.7 YH-16 3.42 × e.sup.−4 2.32 × e.sup.−4 0.00543 0.00570 0.0332  9.67 YH-19 0.0644 0.136 NA NA NA NA YH-20 1.578 5.76 NA NA NA NA YH-22 1.62 × e.sup.−8 1.66 × e.sup.−7 2.31 × e.sup.−6 5.63 × e.sup.−7 3.46 × e.sup.−4  5.89 YH-24 1.97 × e.sup.−3 0.0673 0.0482 0.0762 0.0458 21.9 YH-25 0.593 2.30 NA NA NA NA YH-30 0.0219 0.0368 0.00248 0.171 7.23 73.5 YH-35 0.000426 0.00192 0.00482 0.0642 0.144 42.9 YH-36 3.15 × e.sup.−4 8.46 × e.sup.−5 3.96 × e.sup.−4 1.53 × e.sup.−6 0.0425 14.6 YH-37 9.98 × e.sup.−8 1.45 × e.sup.−7  2.22 e.sup.−5 1.26 × e.sup.−4 5.08 × e.sup.−4 10.3 YH-38 1.56 × e.sup.−6 1.23 × e.sup.−5 2.76 × e.sup.−4 9.02 × e.sup.−4 0.00542 20.6 YH-39 2.99 × e.sup.−5 2.32 × e.sup.−5 2.98 × e.sup.−4 7.90 × e.sup.−4 0.00673 18.5 YH-40 3.59 × e.sup.−6 9.34 × e.sup.−5 3.02 × e.sup.−5 2.20 × e.sup.−4 1.20 × e.sup.−4 20.3 YH-44 0.193 0.641 0.0748 0.306 4.65 17.4 YH-51 0.00781 0.0774 0.00251 0.00202 1.77 12.3 YH-52 5.17 × e.sup.−7 4.66 × e.sup.−8 4.22 × e.sup.−6 5.93 × e.sup.−8 9.67 × e.sup.−5 53.6 YH-53 2.35 × e.sup.−6 5.77 × e.sup.−5 3.56 × e.sup.−5 4.33 × e.sup.−4 1.98 × e.sup.−4 56.3 YH-56 4.47 2.69 13.1 15.4 47.1 35.1 YH-57 2.32 1.87 4.82 40.8 46.7 41.1 YH-58 33.6 40.2 NA NA NA NA YH-60 0.0494 0.0739 0.00285 0.911 3.89  4.81 YH-61 0.189 0.543 NA NA NA NA ENZ 24.8 62.3 20.7 57.3 39.4 NA DOX 0.00104 0.00287 2.55 × e.sup.−5 0.0124 0.00599   0.0333 ENZ: a positive drug enzalutamide; DOX: a positive drug doxorubicin; and NA means not tested for a low activity.

    In Vivo Pharmacodynamic Evaluation of Compound YH-52 in Animals

    (1) Construction of a Mice Model for 22RV1 Prostate Cancer Growth

    [0094] First, a large number of 22RV1 cells were amplified. To ensure the success rate of tumor-bearing, the cell state needs to be adjusted to the optimal state. When the number of the cells was sufficient, the cells were digested and flushed twice with PBS buffer to remove fetal bovine serum (FBS) from the medium to reduce immune rejection. The cells were adjusted to 3000*10.sup.4/mL after counting by a hemocytometer. Then 22Rv1 human prostate cancer cells (1004) were subcutaneously injected into a 4-5 weeks old nod-scid male mice with severe immunodeficiency.

    (2) Grouping and Administration

    Oral Administration Experiment:

    [0095] When the tumor grew to a volume of about 100 mm.sup.3, the mice were randomly divided into 3 groups to make sure that the average tumor volume was the same. The mice in the dosing group were orally gavaged with 0.5 mg/kg and 2 mg/kg of Compound YH-52 per day, and the mice in the control group were given the same volume of normal saline containing DMSO. The body weight of the mice and the length and width of the tumors were measured and recorded every 3 days. The subcutaneous tumors were taken and then photographed at the end of the experiment. The tumor volumes were calculated according to the equation: volume=length×width.sup.2×π/6, and then counted. The experimental results are shown in FIG. 2A, FIG. 2B and FIG. 2C.

    Experiment of Intraperitoneal Injection Administration in Combination with Enzalutamide:

    [0096] When the tumor grew to about 100 mm.sup.3, the mice were randomly divided into 4 groups to make sure that the average tumor volume was the same. The mice in the dosing group were intraperitoneally injected with 0.1 mg/kg of Compound YH-52 per day, the mice in the positive drug group were intraperitoneally injected with 10 mg/kg of enzalutamide per day, the mice in the combination group were intraperitoneally injected with 0.1 mg/kg of Compound YH-52 and 10 mg/kg of enzalutamide per day, and the mice in the control group were given the same volume of normal saline containing DMSO. The body weight of the mice and the length and width of the tumor were measured and recorded every 3 days. The subcutaneous tumors were taken and then photographed at the end of the experiment. The tumor volumes were calculated according to the equation: volume=length×width.sup.2×π/6, and then counted. The experimental results are shown in FIG. 3A, FIG. 3B, FIG. 3C and FIG. 3D.

    (3) Experimental Results

    [0097] As shown in FIG. 2A, FIG. 2B and FIG. 2C, Compound YH-52 could significantly inhibit tumor growth in mice at an oral gavage dose of 0.5 mg/kg and 2 mg/kg. As shown in FIG. 3A, FIG. 3B, FIG. 3C and FIG. 3D, compared to the positive drug enzalutamide (ENZ), Compound YH-52 administrated by intraperitoneal injection (at a dose of 0.1 mg/kg) showed a greater efficacy, and has a significant synergistic effect at a dose of 0.1 mg/kg when being administrated by intraperitoneal injection in combination with ENZ (10 mg/kg).

    [0098] It is foreseeable that pharmaceutically acceptable salts of the compound can produce the same or similar activity.