Dolastatin 10 cyclopeptide derivative and preparation method and application thereof

A technology of dolastatin and derivatives, applied in the direction of cyclic peptide components, peptides, drug combinations, etc., can solve the problems of poor stability, increased compound structure, high toxicity, etc., and achieve the effect of high stability, low toxicity, and low cost

Active Publication Date: 2019-05-24
INNOVATIVE DRUG RES & DEV CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to provide a series of dolastatin 10 cyclic peptide derivatives with rich skeleton structure, increase the diversity of compound structures, and solve the toxicity and poor stability in vivo of dolastatin 10 as an anti-tumor drug and other shortcomings

Method used

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  • Dolastatin 10 cyclopeptide derivative and preparation method and application thereof
  • Dolastatin 10 cyclopeptide derivative and preparation method and application thereof
  • Dolastatin 10 cyclopeptide derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1 Compound 1

[0039]

[0040] Weigh the linear pentapeptide and dissolve it in DMF (1×10 -3 mol / L), ice-water bath cooling, nitrogen protection, and then add DMAP (2 equivalents) in sequence, after the addition, keep the ice-water bath stirring for 5 minutes, then add EDCI (5 equivalents) at once, continue to maintain the ice-water bath reaction 1-2 After hours, the temperature is raised to room temperature and the reaction is about 6 hours until the LC-MS detects that the reaction is complete. Quench with water, extract with ethyl acetate, and wash the organic phase with 10% citric acid aqueous solution, water, saturated brine, and anhydrous Na 2 SO 4 Dry, spin off the solvent under reduced pressure to obtain the crude cyclic peptide. The crude product was separated and purified by preparative HPLC to obtain cyclic peptide compound 1, a white solid (10 mg, 47%). 1 H NMR(400MHz, DMSO-d 6 )δ7.41–7.05(m,5H), 5.43–5.23(m,1H), 4.92–4.65(m,1H), 4.47(dd,J=34.4,23.8Hz,1H...

Embodiment 2

[0041] Example 2 Compound 2

[0042]

[0043] The procedure is the same as in Example 1, white solid (10mg, 35%). 1 H NMR(400MHz, DMSO-d 6 )δ7.24(s,5H), 5.37(dd,J=11.9,7.8Hz,2H), 4.89–4.75(m,1H), 4.68(s,1H), 4.52–4.39(m,1H), 4.34 --4.22(m,1H),4.05(s,1H),3.72--3.54(m,2H),3.23(s,3H),3.07(s,2H),2.95--2.73(m,2H),2.56(s ,4H), 2.45(dd,J=31.6,12.4Hz,2H),2.31–2.16(m,2H),2.06(dd,J=15.2,7.2Hz,6H),1.80–1.66(m,2H), 1.54–1.46(m,3H),1.12(d,J=4.4Hz,4H),1.01–0.87(m,13H).HRMS(ESI; m / z)[M+Na] + calcd for C 35 H 57 N 5 O 7 Na 694.4156, found 694.4106.

Embodiment 3

[0044] Example 3 Compound 3

[0045]

[0046] The procedure is the same as in Example 1, white solid (13 mg, 41%). 1 H NMR(400MHz, DMSO-d 6 )δ7.41–7.11(m,5H), 4.54(ddd,J=28.1,14.9,8.3Hz,1H), 4.32–4.20(m,1H), 4.19–4.09(m,1H), 4.08–4.00( m, 1H), 3.66 (dd, J = 12.2, 6.0 Hz, 1H), 3.48 (t, J = 7.7 Hz, 1H), 3.29 (t, J = 5.1 Hz, 3H), 3.20-3.14 (m, 2H ), 3.13 (s, 2H), 2.92 (dd, J = 12.2, 6.1 Hz, 1H), 2.87–2.77 (m, 1H), 2.33 (ddd, J = 17.8, 11.9, 5.6 Hz, 1H), 2.21– 2.06(m,2H),2.05-1.84(m,4H),1.68(dt,J=15.0,12.8Hz,2H),1.53-1.39(m,2H),1.34(s,2H),1.26(d, J=22.0Hz,8H),1.08–0.75(m,17H).HRMS(ESI;m / z)[M+H] + calcd for C 37 H 60 N 5 O 7 686.4493,found 686.4545.

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Abstract

The invention discloses a novel dolastatin 10 cyclopeptide derivative, a preparation method thereof and application thereof in antitumor drugs. The novel dolastatin 10 derivative with cyclopeptide structure may act as a novel antitumor compound, having good inhibitory effect against tumor cells, especially human colon cancer cells, leukemia cells, osteosarcoma cells and the like. The novel dolastatin 10 cyclopeptide derivative is prepared by converting a linear-chain pentapeptide intermediate, adding an amide condensing agent and carrying out liquid synthetic cyclization. The preparation method provided herein is low in cost, convenient to operate and high in efficiency. The novel dolastatin 10 cyclopeptide derivative has good inhibitory effect against cancers, especially HCT-116 human colon cancer cells, and has high stability and low toxicity; basis is laid for the development of anticancer drugs to treat colon cancer and other cancers.

Description

Technical field [0001] The present invention relates to the field of medicinal chemistry, and relates to a class of cyclic peptide compounds, in particular to a docetoxin 10 cyclic peptide derivative, a preparation method thereof, and application in preparing anticancer drugs. Background technique [0002] The treatment of cancer has always been a difficult problem for humans to overcome, and the mortality rate caused by malignant tumors has also been high, which greatly threatens human life and health. Due to factors such as the complexity of tumor etiology, the drug resistance of tumors and the side effects of anti-tumor drugs, current anti-tumor drugs cannot meet the needs of treatment. Therefore, it is of great significance to design new anti-tumor drugs with high efficiency and low toxicity. [0003] In 1987, the Pettit research group of Arizona State University in the United States isolated and extracted the natural product dolabella auricularia from the marine organism Dola...

Claims

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Application Information

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IPC IPC(8): C07K7/56A61K38/12A61P35/00A61P35/02
Inventor 胡文浩王信冯登科徐新芳钱宇邱晃
Owner INNOVATIVE DRUG RES & DEV CENT
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