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Raubasine derivative, preparation and application thereof

A technology of derivatives and amoline, applied in the field of preparation of antineoplastic drugs, amoline derivatives and preparation

Inactive Publication Date: 2010-08-04
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthesis of new active alkaloid compounds based on the catalytic activity of the enzyme has rarely been reported.

Method used

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  • Raubasine derivative, preparation and application thereof
  • Raubasine derivative, preparation and application thereof
  • Raubasine derivative, preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1 : Preparation of (3α, 15α, 19α)-12-aza-16,17-didehydro-19-methyl-oxoyohimbine-16-carboxylate (compound I-1)

[0021]

[0022] This example relates to a general synthesis method of a class of new amoline derivatives with cytotoxic activity as shown in formula (I). It specifically relates to the synthesis of (3α, 15α, 19α)-12-aza-16,17-didehydro-19-methyl-oxoyohimbine-16-carboxylic acid methyl ester. 12-Azaisosidine (20 mg, 0.0376 mmol) was dissolved in acetic acid buffer (pH 5.0, 2.0 ml), and then β-glucosidase (10 mg) was added to the reaction solution, under nitrogen protection at 37 ℃ and stirred for 24 hours, then the reaction solution was freeze-dried, and the freeze-dried product was added with an appropriate amount of methanol to dissolve and then centrifuged. The supernatant was added to the reaction flask, and glacial acetic acid (32.0 ml) and excess sodium borohydride (21.0 ml) were added under nitrogen protection. mg), reacted at room temperatur...

Embodiment 2

[0025] Example 2 : Preparation of Compounds I-2 and I-3

[0026] According to the method of Example 1, using the corresponding 12-methoxy isosidine and 11-chloro isosidine as raw materials, the compounds I-2 and I- 3.

[0027] Compound I-2: pale yellow solid; yield 51.3%; Rf (chloroform / methanol 15:1) 0.35; ESI-MS m / z[M+H] + 431; 1 H NMR (500MHz, CDCl 3 ): δ7.81 (1H, s, NH), 7.56 (1H, s, H-17), 7.46 (1H, d, J=8.0Hz, H-9), 7.17 (1H, d, J=7.5Hz , H-11), 7.08 (1H, dd, J=7.5, 8.0Hz, H-10), 4.50 (1H, m, J=6.5Hz, H-19), 3.84 (3H, s, CH 3 O-12), 3.75 (3H, s, COOCH 3 -16), 3.60 (1H, dd, J=11.5, 1.5Hz, H-3), 3.11 (1H, dd, J=12.5, 1.5Hz, H-21b), 2.96 (1H, m, H-5a) , 2.92 (1H, m, H-6b), 2.68-2.78 (3H, m, H-6a, 21a, 5b), 2.47-2.59 (2H, m, H-15, 20), 1.53 (2H, m, H-14), 1.41 (3H, d, J=6.5Hz, CH 3 -19).

[0028] Compound I-3: light yellow solid; yield 54.8%; Rf (chloroform / methanol 15:1) 0.38; ESI-MS m / z[M+H] + 371; 1 H NMR (500MHz, CDCl 3 ): δ8.25 (1H, s, NH), 7.73 (1H, s, H-12...

Embodiment 3

[0030] Example 3: Cytotoxic activity of compound I-1 on A549 cells

[0031] A549 (human lung cancer) cells were cultured with RPMI 1640 medium containing 10% fetal bovine serum, 100 U / ml penicillin and 100 U / ml streptomycin. cells in 5×10 per well 3 concentration into a 96-well plate at 37 °C with 5% CO 2 Incubate for 24 hours in a humidified incubator.

[0032] Cell viability was determined by the modified MTT method. After the cells were incubated for 24 hours, the newly prepared dimethyl sulfoxide solution of compound I-1 was added to each well in a concentration gradient, so that the final concentrations of the compound in the wells were 100 μg / ml, 33.3 μg / ml, respectively. 11.1 μg / ml and 3.7 μg / ml. After 72 hours, add 10 microliters of MTT (5 mg / ml) in phosphate buffer, continue to incubate at 37°C for 4 hours, centrifuge for 5 minutes to remove unconverted MTT, and add 200 microliters of dimethyl sulfide to each well. The sulfone was used to dissolve the reduced M...

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Abstract

The invention provides a raubasine derivative and a pharmaceutical salt thereof. The preparation method comprises the following steps of: separating monomolecular glucose from substituted strictosidine under the action of beta-glycosidase; then, reducing by excess sodium borohydride to prepare the raubasine derivative. In the raubasine derivative, a cell toxic activity test of human lung carcinomas and human chronic myeloid leukemia cells in vitro indicates the raubasine derivative has inhibited effect on tumour cell growth, can be applied to preparing medicines for preventing and treating lung cancer and chronic myeloid leukemia and has the following structural general formula (disclosed as the specification).

Description

field of invention [0001] The invention belongs to the fields of enzyme chemistry, medicinal chemistry and pharmacology, and relates to an amoline derivative and a preparation method, as well as the application of the compound in the preparation of antitumor drugs. Background of the invention [0002] Terpene indole alkaloids are a large class of natural products, which have a very wide range of pharmacological activities, such as vinblastine, vincristine and camptothecin, which have anticancer activities. Studies have found that most terpenes Indole alkaloids are transformed from isosidine by different secondary metabolisms, and isosidine synthase (STR) is the key enzyme in the synthesis of isosidine. On the basis of understanding the biogenesis pathway, the researchers conducted in-depth research on the key enzyme isosidine synthase in the biogenesis pathway, and gained a further understanding of its three-dimensional structure and catalytic function (Joachim Stockigt, San...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22A61K31/4375A61P35/02A61P35/00
Inventor 邹宏斌祝华建约阿施·史托克希特俞永平
Owner ZHEJIANG UNIV
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