Tryptophan 7-bit maleimide cyclized derivative as well as preparation method and application thereof

A technology of maleimide and tryptophan, which is applied in the preparation methods of peptides, chemical instruments and methods, drug combinations, etc., can solve the problem that the C-7 position cyclization reaction cannot be realized, the reaction conditions are severe, and the reaction yield is low problems, to achieve the effect of good anti-tumor application prospect, high site selectivity, and simple operation process

Pending Publication Date: 2022-06-24
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has many steps, low reaction yield, and severe reaction conditions. These problems have greatly reduced the progress of the later modification research on Trp-containing polypeptides.
There are many modification methods at present, but the C_C bond modification at the 7th position has not been reported in the literature. Therefore, the prior art cannot realize the cyclization reaction at the C-7 position

Method used

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  • Tryptophan 7-bit maleimide cyclized derivative as well as preparation method and application thereof
  • Tryptophan 7-bit maleimide cyclized derivative as well as preparation method and application thereof
  • Tryptophan 7-bit maleimide cyclized derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: Compound (I a ) preparation

[0047]

[0048] as formula II a Indicated maleimide-containing tryptophan linear polypeptide (general synthetic procedure for cyclic peptide precursor (II)) (67.84 mg, 0.12 mmol), [RhCp*Cl 2 ] 2 (7.4 mg, 0.012 mmol) suspended in 10 mL DCM, then AgNTf was added 2 (18.6 mg, 0.048 mmol) and silver oxide (41.7 mg, 0.18 mmol). The tube was sealed and the mixture was heated to 80°C for 24 hours. Saturated NaCl aqueous solution was added to the reaction mixture, extracted with ethyl acetate, the organic layer was taken, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation at room temperature to obtain the crude product; further purified by silica gel column or preparative silica gel plate (dichloromethane The volume ratio to methanol is 15:1; Rf=0.4), the solvent is collected and spin-dried to obtain formula I a The compound shown is pure 15.0 mg, yield 22%, compound I a Antitumor ac...

Embodiment 2

[0050] Example 2: Compound (I b ) preparation

[0051]

[0052] as formula II b The indicated maleimide-containing tryptophan linear polypeptide (general synthetic procedure for cyclic peptide precursor (II)) (74.89 mg, 0.12 mmol), [RhCp*Cl 2 ] 2 (7.4 mg, 0.012 mmol) suspended in 10 mL DCM, then AgNTf was added 2 (18.6 mg, 0.048 mmol) and silver oxide (41.7 mg, 0.18 mmol). The tube was sealed and the mixture was heated to 80°C for 24 hours. Saturated NaCl aqueous solution was added to the reaction mixture, extracted with ethyl acetate, the organic layer was taken, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation at room temperature to obtain the crude product; further purified by silica gel column or preparative silica gel plate (dichloromethane The volume ratio to methanol is 10:1; Rf=0.3), the solvent is collected and spin-dried to obtain formula I b The compound shown was 11.3 mg of pure product, and the yield was 15%...

Embodiment 3

[0054] Example 3: Compound (I c ) preparation

[0055]

[0056] as formula II c The maleimide-containing tryptophan linear polypeptide shown (general synthetic procedure for cyclic peptide precursor (II)) (114.66 mg 0.12 mmol), [RhCp*Cl 2 ] 2 (7.4 mg, 0.012 mmol) suspended in 10 mL DCM, then AgNTf was added 2 (18.6 mg, 0.048 mmol) and silver oxide (41.7 mg, 0.18 mmol). The tube was sealed and the mixture was heated to 80°C for 24 hours. Saturated NaCl aqueous solution was added to the reaction mixture, extracted with ethyl acetate, the organic layer was taken, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation at room temperature to obtain the crude product; further purified by silica gel column or preparative silica gel plate (dichloromethane The volume ratio to methanol is 20:1; Rf=0.23), the solvent is collected and spin-dried to obtain formula I c The compound shown was 11.23 mg of pure product, and the yield was 35%. ...

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Abstract

The compound disclosed by the invention is catalyzed by rhodium, and maleimide modification is performed by selecting C7 at a site, so that the compound can be obtained under mild and non-polymerization conditions. Compared with the catalytic reaction of copper trifluoromethanesulfonate (II) reported in the literature, the reaction can effectively perform modification, connection and drug modification on the peptide by using C7. The preparation method is simple in operation process, free of guiding groups, high in site selectivity and efficient in reaction, the compound can be prepared through one step, the compound has a good anti-tumor application prospect, and a new scheme is provided for research and development of anti-tumor drugs.

Description

(1) Technical field [0001] The invention relates to a cyclic derivative of tryptophan at No. 7 position maleimidation, and a preparation method and application thereof. (2) Background technology [0002] Polypeptides are important biologically active molecules that have a wide range of applications in medicinal chemistry, biotechnology and chemical biology. Cyclic peptides have attracted extensive attention in the pharmaceutical industry due to their excellent cell penetration, stability, thermal stability, and drug-like properties. Existing simple and efficient methods for creating such peptides are rather limited. Transition metal-catalyzed late-stage functionalization (LSF) of complex molecules with good site specificity and high functional group tolerance provides a facile approach for efficient C-H functionalization / macrocyclization. In recent years, several methods based on late modification of Trp (tryptophan) residues have been successfully developed. The traditio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/02C07K5/083C07K7/02C07K7/06C07K1/02C07D487/18A61K38/07A61K38/06A61K38/08A61P35/00
CPCC07K5/0806C07K7/02C07K5/021C07K7/06C07D487/18A61P35/00A61K38/00
Inventor 姜吉瞳朱勍严佳辉王鹏
Owner ZHEJIANG UNIV OF TECH
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