Dolastatin 10-cyclic peptide derivative and its preparation method and application

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

Active Publication Date: 2021-09-21
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-cyclic peptide derivative and its preparation method and application
  • Dolastatin 10-cyclic peptide derivative and its preparation method and application
  • Dolastatin 10-cyclic peptide derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 Compound 1

[0040]

[0041] Weigh the linear pentapeptide and dissolve it in DMF (1×10 -3 mol / L), cooled in an ice-water bath, protected by nitrogen, then added DMAP (2 equiv.) in turn, kept stirring in the ice-water bath for 5 min after the addition, then added EDCI (5 equiv.) at one time, and continued to maintain the ice-water bath reaction for 1-2 hours, then the temperature was raised to room temperature, and the reaction was carried out for about 6 hours until the reaction was completed by LC-MS detection. Water was added to quench, extracted with ethyl acetate, the organic phase was washed with 10% aqueous citric acid solution, water, saturated brine, and anhydrous Na 2 SO 4 After drying, the solvent was removed under reduced pressure to obtain a crude product of cyclic peptide. The crude product was separated and purified by preparative HPLC to give cyclic peptide compound 1 as a white solid (10 mg, 47%). 1 H NMR (400MHz, DMSO-d 6)δ7.41–7.05(m...

Embodiment 2

[0042] Example 2 Compound 2

[0043]

[0044] The operation procedure was the same as that of Example 1, white solid (10 mg, 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

[0045] Example 3 Compound 3

[0046]

[0047] The operation procedure was the same as that of 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, 6.0Hz, 1H), 3.48 (t, J=7.7Hz, 1H), 3.29 (t, J=5.1Hz, 3H), 3.20–3.14 (m, 2H) ), 3.13 (s, 2H), 2.92 (dd, J=12.2, 6.1Hz, 1H), 2.87–2.77 (m, 1H), 2.33 (ddd, J=17.8, 11.9, 5.6Hz, 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-cyclic peptide derivative, its preparation method and its application in antitumor drugs. The dolastatin 10 derivative with a cyclic peptide structure of the present invention can be used as a new type of anti-tumor compound, and has a good inhibitory effect on tumor cells, especially human colon cancer cells, leukemia cells, osteosarcoma cells and the like. The dolastatin 10-cyclic peptide derivative of the present invention is obtained by transforming a straight-chain pentapeptide intermediate, adding an amide condensation agent, and obtaining through liquid-phase synthesis and cyclization. The preparation method provided by the invention has low cost, convenient operation and high efficiency. The compound of the invention has a good inhibitory effect on cancer, especially HCT-116 human colon cancer cells, has high stability and low toxicity, and lays the foundation for the development of anticancer drugs for treating colon cancer or other types of cancer.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, relates to a class of cyclic peptide compounds, in particular to a dolastatin 10 cyclic peptide derivative, a preparation method thereof, and an application in the preparation of an anticancer drug. Background technique [0002] Cancer treatment has always been a difficult problem for human beings to overcome, and the mortality rate caused by malignant tumors has always been high, which greatly threatens human life and health. Due to the complexity of tumor etiology, the drug resistance of tumors and the toxic and side effects of anti-tumor drugs, the current anti-tumor drugs cannot meet the needs of treatment. Therefore, it is of great significance to design novel antitumor drugs with high efficiency and low toxicity. [0003] In 1987, the Pettit research group of Arizona State University isolated and extracted the natural product dolastatin 10 from the marine organism Dolabella auricularia i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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