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10- deacetylate-9(R)-hydrogenization-1-deoxypaclitaxel analogue and preparation thereof

A paclitaxel analogue and deacetylation technology, which is applied in organic chemistry, drug combination, pharmaceutical formula, etc., can solve the problems of limited collection, low water solubility, drug resistance and side effects, and achieve simple operation, high yield, good selectivity

Inactive Publication Date: 2009-01-28
SHANGHAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, its natural content is very small, its collection is limited, its water solubility is extremely low, and there are problems such as drug resistance and toxic side effects. Therefore, the research on new resources of paclitaxel and its analogues has attracted much attention. The semi-synthesis of paclitaxel and its derivatives with terpene components (Taxoids) as the precursor is one of the main ways to solve the shortage of resources and improve the comprehensive performance

Method used

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  • 10- deacetylate-9(R)-hydrogenization-1-deoxypaclitaxel analogue and preparation thereof
  • 10- deacetylate-9(R)-hydrogenization-1-deoxypaclitaxel analogue and preparation thereof
  • 10- deacetylate-9(R)-hydrogenization-1-deoxypaclitaxel analogue and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1: The specific synthesis steps of 10-deacetyl-9(R)-hydrogenated-9,10-O-isopropylidene-1-deoxypaclitaxel

[0030]

[0031] a. 1-Deoxybaccatin VI1 (419 mg, 0.6 mmol) was dissolved in 20 mL of 95% ethanol, 10 mL of hydrazine hydrate was added, and stirred at room temperature for 15 hours. Neutralize with 0.2N hydrochloric acid, extract with ethyl acetate, wash the organic layer three times with water, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure. The crude product was recrystallized with a mixed solvent of methanol and n-hexane to obtain 2277 mg of colorless transparent crystal 7,9,10,13-tetradeacetyl-1-dehydroxybaccatin VI with a yield of 87%;

[0032] b. Compound 2 (239 mg, 0.5 mmol) was dissolved in 18 mL of anhydrous CH 2 Cl 2 and 1.5 mL anhydrous CH 3 OH, after completely dissolving, add 2,2-dimethoxypropane (0.4mL, 2.0mmol), stir evenly, add Mont K10 to make 24mg, stir at room temperature for 0.5 hour; After the ...

Embodiment 2

[0035] Example 2: The specific synthesis steps of 10-deacetyl-9(R)-hydrogenated-1-deoxypaclitaxel

[0036]

[0037] e. Compound 6 (42 mg, 0.05 mmol) was dissolved in 4 mL of methanol, stirred evenly, and 0.1 mL of 0.1 N HCl solution was added at room temperature, and a large amount of white precipitates appeared. Heat the oil bath to 65°C, transfer to room temperature after 6 hours, add saturated NaHCO 3 The solution was neutralized; extracted with ethyl acetate, the organic layer was washed three times with water, and anhydrous MgSO 4 After drying, the solvent was evaporated under reduced pressure, and the initial product was slowly separated by column chromatography (thin-layer chromatography silica gel, petroleum ether: ethyl acetate = 1:2) to obtain 10-deacetyl-9(R)-hydrogenated-1 - deoxypaclitaxel 34mg, yield rate 86%; 1 H NMR (500Hz, CDCl 3 ): δ1.13(s, 3H, CH 3 ), 1.53 (s, 3H, CH 3 ), 1.55-1.57 (m, 1H), 1.73 (s, 3H, CH 3 ), 1.78 (s, 3H, CH 3 ), 1.88-1.94(m, 2H)...

Embodiment 3

[0038] Example 3: In vitro screening experiment for anti-tumor biological activity

[0039] MTT method: 3-5×10 4 cells / mL cell suspension 100 μL, set at 37°C, 5% CO 2 Inside the incubator. After 24 hours, add sample solution, 10 μL wells, set up double wells, 37 ° C, 5% CO 2 The effect is 72h. Add 20 μL of 5 mg / mL MTT solution to each well, and add the dissolving solution after 4 hours of action, 100 μL / well, put it in an incubator, measure the 570nm OD value with an MK-2 automatic microplate reader after dissolution.

[0040] Table 1 Inhibitory effect of compound 20 and taxol on human tumor cell proliferation in vitro

[0041]

[0042] A549 (human lung cancer cells); A2780 (human ovarian cancer cells).

[0043] It can be seen from Table 1 that compounds 6 and 7 also have inhibitory effects on the growth of human lung cancer cell A549 and human ovarian cancer cell A2780.

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Abstract

The invention relates to a 10-deacetylbaccatin-9(R)-hydrogenation-1-deoxidized paclitaxel analog and a preparation method thereof. The structural formula of the analog is as the right; in the method of the invention, 1-deoxidized baccatin VI is taken as a material for synthesizing the 1-deoxidized paclitaxel analog. The method of the invention maintains the ring skeleton and the necessary functional group of taxanes and selects the taxanes as a semi-synthetic precursor or carries out structure decoration on the taxanes; the obtained output 10-deacetylbaccatin-9(R)-hydrogenation-1-deoxidized paclitaxel analog has the biological activity of antitumor of the natural paclitaxel and has a certain application prospect in the aspects of reducing the multidrug resistance and the side effects of the natural paclitaxel. The method has the advantages of easily obtained materials, simple and convenient operation, good selectivity and high yield.

Description

technical field [0001] The invention relates to a doxytaxel analogue and a preparation method thereof. In particular, it relates to a 10-deacetyl-9(R)-hydrogenated-1-deoxypaclitaxel analogue and a preparation method thereof. technical background [0002] Paclitaxel (trade name Taxol) is a new type of anticancer drug isolated from Taxus plants with unique anticancer activity. Its structural formula is: [0003] [0004] It has a novel structure, a unique mechanism of action, strong activity, and a wide spectrum of action. It has been clinically proven that paclitaxel is a specific drug for the treatment of breast cancer, uterine cancer, pancreatic cancer, and colon cancer. At the end of 1992, it was officially approved by the US FDA as a new drug for the treatment of ovarian cancer and breast cancer. It is one of the best anti-tumor drugs recognized internationally in recent years. However, its natural content is very small, its collection is limited, its water solubili...

Claims

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Application Information

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IPC IPC(8): C07D305/14A61K31/337A61P35/00
Inventor 林海霞袁天海王晓洪王佃龙邵军超靳丹辉
Owner SHANGHAI UNIV
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