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Preparation method for biological active peptide N14-Desacetoxytubulysin H

A technology of biologically active peptides and compounds, applied in the field of medicine, can solve the problems of unsatisfactory synthesis and imperfect synthetic route, etc.

Inactive Publication Date: 2019-04-26
SHENZHEN ELDERLY MEDICAL RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its synthesis is not ideal. So far, there are dozens of documents reported on the chemical synthesis of Tubulysis and its analogues, and most of the synthetic routes are not perfect, so there is a lot of room for further exploration.

Method used

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  • Preparation method for biological active peptide N14-Desacetoxytubulysin H
  • Preparation method for biological active peptide N14-Desacetoxytubulysin H
  • Preparation method for biological active peptide N14-Desacetoxytubulysin H

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Embodiment 1 prepares TUV fragment (2):

[0066] The synthetic route of TUV fragment (2) is as follows:

[0067]

[0068]

[0069] Include the following steps:

[0070] Step 1, the synthesis of compound 10:

[0071] First, compound 9 was prepared according to the literature (Macromolecules, 2012, 45(20): 8172-8192);

[0072] Compound 9 (39g, 378.15mmol) was dissolved in methanol (500mL), benzaldehyde (39mL, 378.15mmol) was added, heated to reflux for 4h, cooled to 0°C in an ice-water bath, and sodium borohydride (43g, 1.13 mol), then stirred the reaction at room temperature for 12 h, concentrated under reduced pressure, added dilute hydrochloric acid to quench the reaction, and then basified the solution with aqueous sodium hydroxide to pH=10, extracted three times with dichloromethane (300 mL), combined the organic phases, Dry over anhydrous sodium sulfate and concentrate under reduced pressure;

[0073] Then add tetrahydrofuran / water (1:1, 600mL) mixed solve...

Embodiment 2

[0102] Example 2 Bioactive Peptide N 14 - Synthesis of Desacetoxytubulysin H:

[0103] Its synthetic route is as follows:

[0104]

[0105]

[0106] Include the following steps:

[0107] Step 1, the synthesis of compound 4:

[0108] Dissolve compound 2 (1g, 1.9mmol) in THF (60mL), add water (3mL) and triphenylphosphine (5.0g, 19mmol), heat to reflux for 3h, cool to room temperature, concentrate under reduced pressure, direct column chromatography Separation (mobile phase: methanol: dichloromethane 1: 20) separation and purification;

[0109] Add anhydrous dichloromethane (100mL), add compound 3 (0.87g, 3.8mmol), EDCI (1.82g, 9.5mmol) and HOBt (1.28g, 9.5mmol), stir well and drop triethylamine (2.6mL , 19mmol), stirred at room temperature for 15h, added water (300mL) to quench the reaction, extracted three times with dichloromethane (200mL), combined organic phases were washed with water (200mL), washed with saturated brine (200mL), separated, and the organic phase A...

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Abstract

The invention discloses a preparation method for a biological active peptide N14-Desacetoxytubulysin H. The preparation method comprises the following steps: preparing a TUV segment (2); preparing thebiological active peptide N14-Desacetoxytubulysin H. The preparation method disclosed by the invention meets green chemical standards, such as utilization of renewable resources, recyclability, low toxicity of used reagents and less environmental pollution after treatment on reaction. The preparation method has the advantages of high total yield, high stereoselectivity, low cost, simple and convenient separation and purification, and suitability for large-scale preparation.

Description

technical field [0001] The invention belongs to the technical field of medicines, in particular, relates to a biologically active peptide N 14 - A process for the preparation of Desacetoxytubulysin H. Background technique [0002] In 2000, et al. (Sasse, F.; Steinmetz, H.; Heil, J.; G.; Reichenbach, H.J.Antibiot.2000, 53, 879.) reported for the first time a small linear tetrapeptide molecule isolated from myxobacteria. Because they mainly act on the tubulin cytoskeleto of cells, this class of compounds is named Tubulysins. [0003] Studies have found that Tubulysins not only have high anticancer activity (N 14 - IC of Desacetoxytubulysin H 50 It is about 100-5000 times that of paclitaxel and more than 10 times that of epothilone B), and can effectively inhibit the growth of drug-resistant cancer cells, but its specific mechanism of action is opposite to that of epothilone and paclitaxel , which promotes the polymerization of tubulin. Although the mechanism of action...

Claims

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Application Information

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IPC IPC(8): C07K5/117C07K1/16
CPCC07K5/1024
Inventor 吴正治龙伯华
Owner SHENZHEN ELDERLY MEDICAL RES INST
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