Anti-cancer active compound depside peptide as derivative of natural product

A technology of depsipeptides and natural products, applied in the field of medical engineering, can solve the problems of poor stability, environmental sensitivity, poor water solubility and the like

Inactive Publication Date: 2007-04-11
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

) its disadvantages are: Cryptophycins series compounds have the disadvantages of poor water solubility and poor stability, are sensitive to the environment in the animal body, are easily decomposed and lose anticancer activity

Method used

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  • Anti-cancer active compound depside peptide as derivative of natural product
  • Anti-cancer active compound depside peptide as derivative of natural product
  • Anti-cancer active compound depside peptide as derivative of natural product

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Total synthesis method: (taking X=O, R=H, Y=NH in CryptophycinsIV series as an example)

[0033] 1. Fragment A (pre-synthesis 1.0eq), fragment D (L-leucic acid TBS protected hydroxyl 1.2eq), add DCC (2.eq), DMAP (cat), CH2Cl2 as solvent; after mixing, stir at room temperature for 6 hours, Silica gel column separation, obtain product (67%)

[0034] 2. The product (1.0eq) obtained in 1 and C fragment (CSI: chlorosulfonyl isocyanate, 1.2eq) were mixed in an ice-water bath at 0°C. After 30 minutes, the solvent was evaporated to dryness under reduced pressure and used directly in the next reaction. Fragment D: (R)-tert-butyl 1-amino-3-(3-chloro-4-methoxyphenyl)propyl-2-ylcarbamate (1.3eq) was added to anhydrous CH2Cl2 of the previous product , Et3N (3.0 eq) was added, followed by stirring at room temperature for 2 hours. The product was isolated on a silica gel column (65%).

[0035] 3. Add 2 product to TFA, CH 2 Cl 2 After stirring at room temperature overnight, the pr...

Embodiment 2

[0038]Other derivatives of the CryptophycinsIV series are all prepared by the method 1.2.3 in the above-mentioned embodiment 2, except that the conversion of the 4 and 8-position O and N atoms is completed when the D and B fragments are synthesized, and the others are all modified after the synthesis of the macrocycle. Corresponding methylation, ethylation, hydroxymethylation, methoxymethylation, and phosphorylation after hydroxymethylation are carried out on the 6-position N atom to obtain respective corresponding derivatives.

[0039] The NMR data of methylation products are as follows:

[0040] 1 HNMR (CDCl 3 ): δ7.39(m, 5H), 7.20(S, 1H), 7.08(d, J=8.4Hz, 1H), 6.88(d, J=8.4Hz, 1H), 6.59(m, 1H), 6.02 (d, J=7.5Hz, 1H), 5.77(d, J=15.7Hz, 1H), 5.65(m, 1H), 5.10(m, 2H), 4.20(m, 1H), 3.90(s, 3H) , 3.72(s, 1H), 3.38(s, 3H), 3.31(m, 2H), 2.96(d, J=7.0Hz, 1H), 2.89(m, 1H), 2.78(m, 1H), 2.57( m, 1H), 2.41(m, 1H), 1.90(m, 1H), 1.75(m, 2H), 1.43(m, 1H), 1.18(d, J=7.0Hz, 3H), 0.91(m...

Embodiment 3

[0043] The derivatives of Cryptophycins I, II, and III series were also prepared by the method 1.2.3 in Example 2 above to complete the total synthesis of 16-membered macrocycles. The difference in the molecule is that the conversion of the 4-position O and N atoms is completed when the D segment is synthesized, and the main difference between the derivatives of the Cryptophycins I, II, and III series is the difference in the C segment. In the derivatives of the Cryptophycins I series, the C fragment is L-serine, and the hydroxyl group of the hydroxymethyl group on the 6-position C is further methylated and phosphorylated to obtain each corresponding derivative.

[0044] The C-segment of the derivatives of Cryptophycins II series is L-asmandoamide.

[0045] The C fragment of the derivative of Cryptophycins III series is L-methionine.

[0046] The above-synthesized Cryptophycins series of compounds can be used to conduct research on their anti-cancer activity and study their a...

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PUM

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Abstract

The present invention relates to medicine engineering technology, and is especially anticancer active compounds depside peptides as the derivatives of natural production. The compounds of the present invention, Cryptophycins I-V, are prepared through one synthesis path including separate synthesis of four molecular fragments, connecting these fragments to form 16-element macrolide compound, and final double bond epoxidation. Compared with Cryptophycin 52, Cryptophycins I-V have specific group introduced to some specific position and thus raised water solubility and stability.

Description

technical field [0001] The invention relates to a compound in the technical field of medical engineering, in particular to a derivative of an anticancer active compound depsipeptide natural product. Background technique [0002] Cancer is one of the major threats to modern human health. Although great efforts have been made to conquer cancer in recent decades, it is still far from the goal of conquering cancer, and cancer is still one of the important causes of human death. Anticancer active compounds (Cryptophycins) derivatives, Cryptophycins are a class of depsipeptide natural products with sixteen-membered macrocyclic structure characteristics, named for their good antibacterial activity against the filamentous fungus cryptococcus. [0003] In recent years, with the breakthrough and development of human genomics, molecular and cell biology, and new drug design technology, people have a deeper understanding and understanding of the pathology and mechanism of cancer on a m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/06C07D419/06C07F9/09A61K31/395C07D291/00C07D273/00
Inventor 张健存刘文陆傅磊陈尧彭英丹
Owner SHANGHAI JIAO TONG UNIV
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