Gambogic acid derivatives as well as preparation method and application thereof

A technology of gambogic acid and derivatives, applied in the fields of gambogic acid derivatives and their preparation and application, can solve the problems of poor water solubility and low bioavailability of gambogic acid

Inactive Publication Date: 2014-03-05
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, gambogic acid has poor water solubility and low bioavailability. In order to find compounds with better biological activity, scientists have shown strong interest in the chemical modification of related structural parts of gambogic acid. Cai (US2003078292, WO0044216) and Guo Qinglong ( CN1927861, CN102503951), etc. conducted in-depth research, and the research results showed that the structural modification of C-30 would not cause a decrease in the biological activity of the compound, but it could improve water solubility and bioavailability, and its modification was limited to the esterification and acylation of the carboxyl group. reaction

Method used

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  • Gambogic acid derivatives as well as preparation method and application thereof
  • Gambogic acid derivatives as well as preparation method and application thereof
  • Gambogic acid derivatives as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] The preparation of embodiment 1 methyl gambogic acid and methyl isogambogic acid

[0023] At room temperature, under nitrogen protection, 3g gambogic acid GA (4.78mmol) was dissolved in dichloromethane (50mL), EDCI (1.83g, 9.55mmol, 2eq), DMAP (1.17g, 9.55mmol, 2eq ), finally added methanol 1.93mL (47.8mmol, 10eq), and reacted at room temperature for 2h. Add water to quench the reaction, extract with dichloromethane, combine the organic phases, wash with saturated saline solution, dry over anhydrous sodium sulfate, spin dry, and purify by column chromatography to obtain a yellow solid (methyl esterification product 1 and isomerization methyl ester product 2) .

[0024] Compound 1: orange solid, melting point, 98°C; 1 H NMR (400MHz, CDCl 3 )δ12.85(s, 1H), 7.54(d, J=6.9Hz, 1H), 6.68(d, J=10.1Hz, 1H), 5.93(td, J=7.4, 1.3Hz, 1H), 5.44( d, J=10.2Hz, 1H), 5.10-5.00(m, 2H), 3.48(dd, J=6.8, 4.6Hz, 1H), 3.43(s, 3H), 3.31(dd, J=14.6, 8.0Hz , 1H), 3.15(dd, J=14.6, 5.3Hz, 1H),...

Embodiment 2

[0026] Embodiment 2 Preparation of reduced compound 3 and reduced diol compound 5

[0027] Under nitrogen protection, 1.313g of compound 1 (2.05mmol, leq) was dissolved in dichloromethane, and 5.1mL (6.14mmol, 3eq) of Dibal-H was added dropwise to the solution at -78°C, and supplemented after 3 hours. Add 1.7mL (1eq) Dibal-H, and continue the reaction for 1 hour. Quenched with saturated sodium potassium tartrate solution, extracted with ethyl acetate, combined organic phases, washed with saturated saline solution, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to obtain compounds 3 and 5.

[0028] Compound 3: orange-yellow amorphous solid; 1 H NMR (400MHz, CDCl 3 )δ13.02(s, 1H), 7.65(d, J=7.2Hz, 1H), 6.68(d, J=10.1Hz, 1H), 5.96(t, J=6.8Hz, 1H), 5.43(d, J=10.1Hz, 1H), 5.12-5.00(m, 2H), 3.54(s, 3H), 3.33(dd, J=14.8, 7.8Hz, 1H), 3.29-3.26(m, 1H), 3.23(dd , J=15.4, 4.4Hz, 1H), 3.04(d, J=5.6Hz, 1H), 2.93-2.88(m, 1H), 2.84(dd, J=16.4, 6.4H...

Embodiment 3

[0030] The preparation of embodiment 3 perreduction compound 4a and 4b

[0031] With embodiment 2, difference is that the addition of Dibal-H is 6eq, obtains compound 4a, 4b and 5.

[0032] Compound 4a: orange-yellow amorphous solid, 1 H NMR (400MHz, CDCl 3 )δ12.14(s, 1H), 6.63(d, J=10.1Hz, 1H), 5.42(d, J=10.1Hz, 1H), 5.31-5.22(m, 1H), 5.17(t, J=6.6 Hz, 1H), 5.06(t, J=7.0Hz, 1H), 4.08(d, J=11.7Hz, 1H), 3.64-3.60(m, 2H), 3.34(dd, J=11.7, 7.2Hz, 1H ), 3.28(d, J=6.7Hz, 2H), 2.64(br, 2H), 2.43(d, J=9.6Hz, 1H), 2.36(dd, J=13.6, 10.0Hz, 1H), 2.29(d, J=14.4Hz, 1H), 2.13(dd, J=13.5, 7.0Hz, 1H), 2.05(dd, J=15.7, 7.8Hz, 2H), 1.97(dd, J=12.5, 4.5Hz, 1H), 1.90(d, J=10.2Hz, 1H), 1.84-1.73(m, 12H), 1.69(s, 3H), 1.65(s, 3H), 1.63-1.58(m, 1H), 1.56(s, 3H) , 1.46 (s, 3H), 1.42 (s, 3H) ppm; 13 C NMR (101MHz, CDCl 3 )δ 196.2, 160.5, 158.2, 155.6, 140.4, 131.9, 131.8, 124.7, 123.8, 121.8, 120.2, 115.9, 107.4, 102.2, 101.8, 90.0, 86.5, 82.5, 81.0, 76.5, 64.14, 51.3 , 34.1, 30.3, 29.8, 27.4...

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Abstract

The invention relates to gambogic acid derivatives as well as a preparation method and application thereof. The derivatives with the structures are mainly characterized in that a plurality of C-30 carboxyl reduced and aminated compounds are obtained for the first time through modifying the C-12, C-29 and C-30 positions of gambogic acid. Biological tests prove that the compounds have anti-tumor activity and can be used for preparing anti-tumor drugs, and the derivatives can be used as lead compounds so that an approach is developed for finding novel anti-tumor drugs. In the formula, R1 is hydroxyl, alkyl or benzyl; R2 is non-substituent, hydroxyl or alkyl, and at the moment, C-12 can form a single bond or double bonds with oxygen; R3 and R4 are respectively methyl, ester group, methylene alcohol, formyl and substituted amino group.

Description

technical field [0001] The invention relates to a novel gambogic acid derivative with anti-tumor activity and its preparation method and application. Background technique [0002] Gambogic acid (gambogic acid, GA) is a natural product isolated from the traditional Chinese medicine Gambogic with strong anti-tumor activity. Research on the antitumor effect of gambogic acid shows that it can selectively kill cancer cells without affecting the normal hematopoietic system and white blood cells, which will provide a way to find new anticancer drugs. Gambogic acid, as an antitumor drug with high efficiency and low toxicity, exerts antitumor effects through different mechanisms, including induction of cell cycle arrest and apoptosis, inhibition of telomerase and topoisomerase activities, anti-tumor angiogenesis and tumor Metastasis, reversal of multidrug resistance, etc. However, gambogic acid has poor water solubility and low bioavailability. In order to find compounds with bette...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/20A61P35/00A61P35/02
CPCC07D493/20
Inventor 陈莉冯俊俊马国贞张春霞李鹏飞
Owner NANKAI UNIV
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