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Garcinia derivative and preparation method and medicinal application thereof

A pharmacy and compound technology, applied in the field of Garcinia derivatives and their preparation, can solve the problems of limited structure modification space, lack of druggability characteristics, etc., and achieve the effect of improving gastrointestinal absorption, novel structure and excellent activity

Active Publication Date: 2012-06-20
CHINA PHARM UNIV
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  • Abstract
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  • Application Information

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Problems solved by technology

(Organic & Biomolecular Chemistry 7 (2009) 4886-4894; European Journal of Medicinal Chemistry 46 (2011) 1280-1290.) It has been reported in the literature that gambogic acid structure simplified II, although it retains certain anti-tumor activity, it does not Has good druggability characteristics, in addition, the synthesis method of this type of compound limits its structural modification space

Method used

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  • Garcinia derivative and preparation method and medicinal application thereof
  • Garcinia derivative and preparation method and medicinal application thereof
  • Garcinia derivative and preparation method and medicinal application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] 3,3a,4,5-tetrahydro-1,11-bis(3-methylbut-2-en-1-yl)-4-bromomethyl-8,10-dihydroxy-1,5-ylidene Methylbridge-1H, 7H-furo[3,4-d]xanthene-7,13-dione (CPUYZ001)

[0054]

[0055] (1) Preparation of 1,5-dihydroxy-3,6-bis[(2-methylbut-3-yn-2-yl)oxy]-9H-xanthene-9-one

[0056] Dissolve 1,3,5,6-tetrahydroxy-9H-xanthene-9-one (5.2g, 20mmol) in acetone (100mL), add potassium carbonate (8.28g, 60mmol), potassium iodide (9.96g, 60mmol ), ketone iodide (382mg, 2mmol) and 3-chloro-3-methylbut-1-yne (6.7mL, 60mmol), heated to 60°C for 1h. After filtration, the filtrate was concentrated, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain 1.19 g of a yellow solid, yield 15.2%, m.p.149-150°C. 1 H NMR (300MHz, CDCl 3 ): δ1.75(s, 6H, 2×-C H 3 ), 1.79(s, 6H, 2×-C H 3 ), 2.71(d, 2H, 2×-C≡C H ), 5.84(s, 1H, Ar-O H ), 6.66 (d, J=2.4Hz, 1H, Ar- H ), 6.91 (d, J=2.4Hz, 1H, Ar- H ), 7.54 (d, J=9.0Hz, 1H, Ar- H ), 7.76 (d, J=9.0Hz, 1...

Embodiment 2

[0064] 3,3a,4,5-tetrahydro-1,11-bis(3-methylbut-2-en-1-yl)-4-iodomethyl-8,10-dihydroxy-1,5-ylidene Methylbridge-1H, 7H-furo[3,4-d]xanthene-7,13-dione (CPUYZ002)

[0065]

[0066] (1) (E)-1-hydroxy-5-((4-iodobut-2-en-1-yl)oxy)-3,6-bis[(2-methylbut-3-ene-2 Preparation of -yl)oxyl]-9H-xanthene-9-one

[0067] (E)-1-hydroxyl-5-((4-bromobut-2-en-1-yl)oxy)-3,6-bis[(2-methylbut-3-en-2-yl )Oxy]-9H-xanthene-9-one (200mg, 0.378mmol) was dissolved in acetone (10mL), sodium iodide (114mg, 0.756mmol) was added, and reacted at room temperature. After TLC detection, the reaction solution was filtered after the raw materials disappeared, the filtrate was concentrated, and the residue was chromatographed (petroleum ether: ethyl acetate = 8:1) to obtain 191 mg of a yellow oil, with a yield of 87.2%. 1 HNMR (300MHz, CDCl 3 ): δ1.51(s, 12H, CH 3 ×4), 3.79(d, 2H, CH 2 ), 4.56 (d, 2H, CH 2 ), 5.05~5.35(m, 4H, CH=C H 2 ×2), 5.95~6.15(m, 4H, C H =CH 2 ×2, C H =CH×2), 6.36(d, J=2.1Hz, 1H...

Embodiment 3

[0071] 3,3a,4,5-tetrahydro-1,11-di(3-methylbut-2-en-1-yl)-4-thiocyanatomethyl-8,10-dihydroxy-1,5 -Methylenebridge-1H, 7H-furo[3,4-d]xanthene-7,13-dione (CPUYZ003)

[0072]

[0073] Prepared according to the method of Example 2, using potassium thiocyanide instead of sodium iodide, and 95% ethanol instead of acetone as solvent to obtain 60 mg of yellow oil, with a two-step yield of 30.4%. IR (KBr, cm -1 ): 2968, 2908, 2155, 1739, 1638, 1595, 1431, 1371, 1223, 1134, 826; 1 H NMR (300MHz, CDCl 3 ): δ1.10~1.81(m, 12H), 2.35~2.75(m, 4H), 2.90(m, 1H), 3.25(m, 2H), 3.65(d, 2H), 3.92(m, 1H), 4.29(m, 1H), 4.47(m, 1H), 5.18(m, 1H), 6.02(s, 1H), 7.07(d, J=6.9Hz, 1H), 12.30(s, 1H); EI-MS (m / z)507[M] + , 479, 448, 396

[0074] ESI-HRMS(m / z)calcd for C 28 h 29 NO 6 S[M+H] + , 508.1716, Found, 508.1768.

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Abstract

The invention relates to the field of medicinal chemistry, in particular to a garcinia derivative (I), a preparation method thereof and the application of the derivative in pharmacy. The derivative is a structural analogue of a garcinia natural product such as gambogic acid and has the molecular weight which is lower than that of the gambogic acid, and hetero atoms and hydrophilic groups are introduced or further salified, so that the absorbability of a gastrointestinal tract is improved; and the derivative has an antitumor effect and can be used for preparing antitumor medicaments.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of Garcinia derivatives, a preparation method thereof and an application in pharmacy. The derivative is a structural analogue of gambogic acid, a natural product of the genus Garcinia, has antitumor effect, and can be used for preparing antitumor drugs. Background technique [0002] Gambogic acid, a natural product, is extracted from the colloidal resin secreted after the trunk of the genus Garcinia is split, and is an important anti-tumor active ingredient in the gamboge resin. Studies have shown that gambogic acid can selectively inhibit the growth of transplanted tumors within the effective dose range, and its anti-tumor effect is different from that of general chemotherapy drugs. It can selectively kill a variety of tumor cells, while for normal hematopoietic System and immune function had no significant effect. Gambogic acid can regulate the expression of a varie...

Claims

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Application Information

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IPC IPC(8): C07D493/10C07D493/20A61K31/352A61K31/4025A61K31/453A61K31/496A61K31/5377A61P35/00
Inventor 尤启冬张晓进李想刘晓蓉孙昊鹏汪小涧郭青龙
Owner CHINA PHARM UNIV
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