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A kind of preparation method and application of 4-position splicing nitrogen mustard derivatives of brefeldin a

A technology of feldspar and its derivatives, which is applied in the fields of natural medicine, medicinal chemistry, and medicine, and can solve the problems of lack of specificity in cell action, large toxic and side effects, and unsatisfactory therapeutic effects, etc.

Active Publication Date: 2021-02-26
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of drug is widely used clinically, but its toxic and side effects are relatively large, and it lacks specificity for cell action, and with the occurrence of tumor drug resistance in recent years, the therapeutic effect is not satisfactory. Chemical modification, improving its curative effect has very important value

Method used

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  • A kind of preparation method and application of 4-position splicing nitrogen mustard derivatives of brefeldin a
  • A kind of preparation method and application of 4-position splicing nitrogen mustard derivatives of brefeldin a
  • A kind of preparation method and application of 4-position splicing nitrogen mustard derivatives of brefeldin a

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Experimental program
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Effect test

Embodiment 1

[0020]

[0021] Take brefeldin A intermediate 3 (32mg, 0.08mmol), dissolve in dichloromethane (2.5ml), add benzoic acid mustard (21mg, 0.08mmol), EDCI (29mg, 0.15mmol) and catalytic The amount of DMAP was stirred at room temperature for the reaction, the progress of the reaction was monitored by TCL, and the reaction was terminated after 24 h. The reaction solution was poured into 20ml of ice-water mixture, extracted with dichloromethane (30ml×3), washed with saturated saline solution, dried over anhydrous sodium sulfate, recovered dichloromethane, passed through a silica gel column (petroleum ether: ethyl acetate = 5: 1), to obtain intermediate 5a, then dissolve 5a in anhydrous THF, remove the 7-position TBS protecting group with TBAF in THF solution, and separate through silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain Yellow oil 6a, yield 23%. HR-MS (ESI,M+Na) + m / zcalcd for C 35 h 38 Cl 2 N 4 o 3 H:546.1784,found 546.1745. 1 H NMR (400MHz, DMSO...

Embodiment 2

[0023]

[0024] Compound 6b was prepared according to the synthesis method of Example 1. Yellow oil, yield 32%. HR-MS(ESI,M+H)m / z: calcd for C 36 h 40 Cl 2 N 4 o 3 H:566.2435,found 566.2391. 1 H NMR (400MHz, DMSO-d 6 ): δ(ppm)7.27(1H,dd,J=15.8,3.3Hz,C 3 -H),7.04(2H,d,J=8.6Hz,Ar-H),6.68(2H,d,J=8.6Hz,Ar-H),5.71(1H,m,C 11 -H),5.59(1H,dd,J=15.8,1.6Hz,C 2 -H),5.20-5.26(2H,m,C 4 ,C 10 -H),4.75(1H,m,C 15 -H),4.56(1H,s,OH),4.07(1H,m,C 7 -H),3.70(8H,m,-NCH 2 CH 2 Cl),0.74-2.49(21H,m,-CH 2 CH 2 CH 2 -,C 5 ,2C 6 ,2C 8 ,C 9 ,2C 12 ,2C 13 ,2C 14 -H,CH 3 ). 13 C NMR (100MHz, DMSO-d 6): δ (ppm) 172.4, 165.4, 149.3, 145.0, 137.2, 130.2, 129.9, 129.8, 129.8, 117.4, 112.4, 112.4, 76.4, 71.7, 70.8, 52.7, 52.7, 49.6, 43.4, 43.3, 41.6, 4 40.9, 33.9, 33.8, 33.4, 31.8, 27.2, 26.8, 21.1.

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Abstract

The invention belongs to the field of natural medicine and medicinal chemistry, and relates to a preparation method and uses of a class of brefeldin A derivative containing chlormethine linked at site4 and having antitumor activity, wherein the brefeldin A derivative containing chlormethine linked at site 4, and the pharmaceutically acceptable salt have a structure represented by the following general formula I, and n is defined in the claim and specification.

Description

technical field [0001] The invention belongs to the technical field of medicine, relates to the fields of natural medicine and medicinal chemistry, in particular to a nitrogen mustard derivative at the 4-OH position of brefeldin A. It specifically relates to these derivatives splicing DNA alkylating agent nitrogen mustard compounds at the 4-OH position of brefeldin A, their preparation methods and their application in the preparation of antitumor drugs. Background technique [0002] Brefeldin A (brefeldin A, BFA) is a secondary metabolite of Ascomycetes (Ascomycetes), which belongs to macrolide antibiotics, also known as clinomycin or ascodiosporin. It was isolated from the fermentation broth of Penicillium decumbens by Singleton et al. in 1958. Brefeldin A, prismatic crystal, white, insoluble in petroleum ether, chloroform, water, easily soluble in ethyl acetate, acetone and methanol. Pharmacological studies have shown that brefeldin A has pharmacological activities such ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D313/00A61K31/365A61P35/00A61P35/02
CPCC07D313/00
Inventor 李达翃华会明李占林李佳李昊楠王茗莹焦润伟
Owner SHENYANG PHARMA UNIVERSITY
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