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Hairpin polyamide modified by chiral (S)-beta-hydroxyl-gamma-amino acid and application for same

A hairpin polyamide and amino acid technology, which is applied to the application field of preparing antitumor drugs, can solve the problems of no polyamide regulation of c-kit gene, no specific recognition function, etc., so as to shorten synthesis time and save research and development costs. , the effect of improving the synthesis efficiency

Active Publication Date: 2013-07-24
杭州庆正鸿科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Through the above search and analysis of the background information related to the present invention, it is found that: there is no report on the use of polyamide to regulate the c-kit gene; S gamma β-OH ) polyamides specifically recognize the c-kit promoter region DNA sequence and inhibit tumor cell apoptosis

Method used

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  • Hairpin polyamide modified by chiral (S)-beta-hydroxyl-gamma-amino acid and application for same
  • Hairpin polyamide modified by chiral (S)-beta-hydroxyl-gamma-amino acid and application for same
  • Hairpin polyamide modified by chiral (S)-beta-hydroxyl-gamma-amino acid and application for same

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: the preparation of compound II

[0052]

[0053] Table 1: Reagents and their abbreviations used in solid-phase synthesis reactions

[0054]

[0055]

[0056] Proceed as follows:

[0057] 1) Activation: Weigh the Fmoc protected β-alanine-Clear resin (SPS-1, 1.00g, 0.4mmol, Peptides International) shown in formula (8) and add it to the solid phase reaction tube of the solid phase reaction device , nitrogen protection, and then add 5mL of DMF to fully bubble nitrogen for 30min to activate the resin;

[0058] 2) Deprotection: first prepare 3 mL of 20% (v / v) piperidine / DMF (both piperidine and DMF are treated anhydrous solvents), and add it to the solid-phase reaction tube of step 1) under nitrogen protection, Fully bubbling reaction for 15 minutes, remove the amino protecting group on β-alanine, remove the solvent in the reaction tube, rinse twice with 3mL anhydrous dichloromethane, rinse once with 2mL anhydrous DMF, each time Drain the solvent af...

Embodiment 2

[0099] Embodiment 2: the preparation of compound III

[0100]

[0101] The operation steps from step 1) to step 21) are the same as in embodiment 1.

[0102] Take the intermediate (IIa=IIIa) of step 21) and the resin with the target polyamide out of the solid-phase reaction tube, put it into a reaction bottle, add 20mL of Dp, and react overnight at 55°C in an oil bath to stop the reaction. Filtrate, collect the filtrate, remove Dp under vacuum to obtain the intermediate (IIIb) of hairpin polyamide (III) protected by chiral hydroxyl and amino groups;

[0103]

[0104] Then, under the protection of nitrogen, 3 mL of deprotection reagent TFA / TMS / TIS / H with a weight ratio of 91:3:3:3 was added to the above intermediate 2 O mixed solution, react at room temperature for 1h to remove the tert-butyl group on the hydroxyl group and the tert-butoxycarbonyl group on the amino group, remove the solvent under vacuum, dissolve the product in dichloromethane, adjust to acidity with 5m...

Embodiment 3

[0105] Example 3: Native-PAGE analysis of the interaction between polyamide and c-kit gene promoter region sequence

[0106] (1) Preparation of 16% non-denaturing polyacrylamide gel (16% Native-PAGE, Table 2): used to investigate the nature of the interaction between the compound and the DNA sequence of the c-kit promoter region.

[0107] Table 2: 16% Native-PAGE recipe

[0108]

[0109]

[0110] (2) Native-PAGE electrophoresis conditions: 100V pre-electrophoresis for 30min. After adding the sample, the voltage was 150V, and the electrophoresis was stopped after 3 hours. Keep at 4°C during electrophoresis. 2 μL of SYBR Gold, stained with the staining solution in the dark for 30 minutes, and rinsed twice with deionized water. Then use the UV gel imaging system to analyze, the results are shown in Image 6 .

[0111] From the analysis of gel results: compounds II and III have obvious effects on DNA, which is concentration-dependent.

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Abstract

The invention provides a hairpin polyamide compound (I) modified by chiral (S)-beta-hydroxyl-gamma-amino acid, and an application for the same in preparation of anti-tumour medicines. The compound is of a hairpin structure, and contains (S)-beta-hydroxyl-gamma-amino acid residue (S gamma beta-OH) with a specific identification function for the basic group T of DNA (deoxyribonucleic acid); additionally, the compound further contains common N-methylpyrrole residue (Py), N-methylimidazole residue (Im), gamma-amino acid residue and beta-alanine residue. Experiments indicate that the hairpin polyamide compound provided by the invention has a strong killing effect on tumour cells BEL7402 (liver cancer) and MKN45 (poorly-differentiated gastric cancer), and the compound III is the strongest in expression, and has essential significance on research and development for anti-tumour gene targeted medicines down-regulated by chirally-modified polyamide mediate c-kit gene.

Description

(1) Technical field [0001] The invention relates to a chiral (S)-β-hydroxyl-γ-amino acid modified hairpin polyamide compound and its application in the preparation of antitumor drugs. (2) Background technology [0002] Polyamide (polyamide) generally consists of 2-3 different five-membered aromatic heterocycles: N-methylpyrrole (Py), N-methylimidazole (Im) and 3-hydroxy-N-methylpyrrole (Hp). ; It is a synthetic small molecular compound that can specifically recognize bases in a DNA minor groove, two or hairpin aromatic amino acids antiparallel, side by side and a predetermined DNA base sequence in a close 1:1 manner ( figure 1 ), that is, N-methylpyrrole (Py) tends to recognize T, A, and C bases; N-methylimidazole (Im) is the reading element for G bases; and 3-hydroxy-N-methylpyrrole ( Hp) can specifically recognize T. So far, people have been able to use Im / Py pairings to identify G·C base pairs; conversely, a Py / Im pair can bond with C·G; C and C·G are distinguished. M...

Claims

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Application Information

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IPC IPC(8): C07D403/14A61K31/4178A61P35/00
Inventor 张文吴艳玲梁静陈冰佳
Owner 杭州庆正鸿科技有限公司
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