Cyclic peptide compounds and application thereof

A technology of cyclic peptide compounds and solvates, which is applied in the field of medicinal chemistry and can solve problems such as apoptosis of cancer cells

Inactive Publication Date: 2015-12-09
GUANGZHOU KAIMO BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Experiments have shown that selective inhibitors of histone deacetylation type I enzymes can increase the acetylation level of chromatin histones, thus leading to the activation of expression of specific genes, and correspondingly leading to terminal differentiation of cells or apoptosis of cancer cells

Method used

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  • Cyclic peptide compounds and application thereof
  • Cyclic peptide compounds and application thereof
  • Cyclic peptide compounds and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086]

[0087] Step 1. Synthesis of compound b

[0088]

[0089] Fmoc-L-Ala (3.11g, 10.0mmol), EDCI (1.91g, 10.0mmol) and DMAP (50mg, 0.406mmol) were dissolved in anhydrous dichloromethane (38mL), and DIPEA (1.6mL , 10.0mmol) and compound a (3.18g, 6.15mmol), stirred at room temperature for 12h, diluted with dichloromethane, the reaction solution was washed with sodium bicarbonate solution (70mLx3), the organic phase was washed with saturated brine, anhydrous sodium sulfate After drying and concentration, the residue was subjected to silica gel column chromatography to obtain compound 9 (4.49 g, 90%) as a pale yellow solid. [α] 20 D :-15.0 (c1.10, CHCl 3 ). 1 HNMR (400MHz, CDCl 3 ): δ7.73(d, J=7.6Hz, 2H), 7.57(m, 2H), 7.38(dd, J=7.4Hz, 2H), 7.30(dd, J=7.4Hz, 2H), 7.37-7.13 (m,15H),5.82and5.73(m,1H),5.65(dd,J=13.6,7.2Hz,1H),5.50(dd,J=15.2,7.2Hz,1H),5.31(d,J= 8.8Hz, 1H), 4.36(t, J=6.8Hz, 2H), 4.25(dd, J=9.2, 4.6Hz, 1H), 4.21(t, J=7.2, 1H), 4.12(t, J=8.4 Hz, 2H), 2...

Embodiment 2

[0102] Embodiment 2, the synthesis of compound 1-2

[0103] The synthesis method is as in Example 1.

[0104] [α] 20 D =8.6(c0.20, CHCl 3 ). 1 HNMR (400MHz, CDCl 3 )δ8.55(s,1H),8.10(s,1H),6.92(q,J=7.0Hz,2H),6.51(d,J=10.0Hz,1H),5.82–5.61(m,2H), 5.53(dd, J=15.6,6.8Hz,1H),5.20(dd,J=17.4,8.0Hz,1H),4.73(dd,J=10.2,3.8Hz,1H),4.32(dd,J=17.7, 4.1Hz,1H),2.88–2.76(m,2H),2.73–2.60(m,3H),2.47–2.33(m,2H),2.30(d,J=6.7Hz,3H)ppm. 13 CNMR (125MHz, CDCl 3 )δ169.5, 168.8, 167.2, 163.2, 158.1, 148.0, 134.2, 132.0, 128.5, 127.0, 124.2, 71.8, 40.6, 40.2, 37.2, 31.3, 31.0ppm. HRMS (ESI) Calcdm / zforC 36 h 43 N 8 o 10 S 4 [(M+H) + ]875.1985, found 875.1986.

Embodiment 3

[0105] Embodiment 3, the synthesis of compound 1-3

[0106] The synthesis method is as in Example 1.

[0107] [α] 20 D =11.6(c0.20, CHCl 3 ). 1 HNMR (400MHz, CDCl 3 )δ8.57(s,1H),8.13(s,1H),6.94(q,J=7.1Hz,2H),6.51(d,J=10.2Hz,1H),5.85–5.65(m,2H), 5.54(dd, J=15.6,6.8Hz,1H),5.20(dd,J=17.6,8.2Hz,1H),4.75(dd,J=10.2,3.8Hz,1H),4.33(dd,J=17.7, 4.1Hz, 1H), 2.90–2.75(m, 1H), 2.70–2.60(m, 3H), 2.48–2.35(m, 2H), 2.29(m, 1H), 1.82(d, J=7.1Hz, 3H ),0.80(t,J=6.8Hz,3H)ppm. 13 CNMR (125MHz, CDCl 3 )δ169.7, 169.1, 167.3, 163.5, 158.3, 148.0, 134.4, 132.1, 128.6, 127.0, 124.2, 71.8, 57.0, 40.7, 40.2, 37.3, 31.5, 31.2, 19.0, 16.3, ppm.HRMS( / ESI)Calcdm 40 h 51 N 8 o 10 S 4 [(M+H) + ]931.2611,found931.2612.

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Abstract

The invention discloses cyclic peptide compounds adopting a chemical structure shown in the general formula I or pharmaceutically acceptable salt, isomers, racemes, pro-drugs or solvates of the cyclic peptide compounds. Compared with a positive control (SAHA), the compounds have remarkable activity for inhibiting deacetylation of HDAC enzymes (mainly include HDAC1, HDAC2, HDAC3, HDAC8 and HDAC11) closely related with tumor proliferation and metastasis as well as remarkable activity for inhibiting tumor cell growth.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a cyclic peptide compound and its application. Background technique [0002] Histone acetylation plays a very important role in the process of DNA transcription, replication and repair of chromosomes. Histone acetylation and deacetylation of chromatin is one of the key links in regulating gene expression, and abnormal gene expression is the molecular biological basis of tumors and some genetic and metabolic diseases. The degree of acetylation of histone is coordinated and controlled by histone acetylase (HAT) and histone deacetylase (HDAC). Histone deacetylases (HDACs) are a group of biological agents that regulate chromatin reorganization, transcriptional activation or repression, cell cycle, cell differentiation, and apoptosis by inducing histone deacetylation at the level of cellular chromatin. It is an enzyme with biological effects, especially related to the re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/097C07K5/03C07K5/037A61K38/06A61K38/07A61P35/00A61P35/02A61P25/28A61P31/18A61P3/10A61P33/06
CPCC07K5/12Y02A50/30
Inventor 李西才
Owner GUANGZHOU KAIMO BIOTECH CO LTD
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