Synthesis and biological activity evaluation of dolastatin 10 analogues with N-terminal modifications

被引：15

作者：

Wang, Xin ^{[1
]}

Dong, Suzhen ^{[1
]}

Feng, Dengke ^{[1
]}

Chen, Yazhou ^{[1
]}

Ma, Mingliang ^{[1
]}

Hu, Wenhao ^{[1
]}

机构：

[1] East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Dept Chem, Sch Chem & Mol Engn, Shanghai 200062, Peoples R China

来源：

TETRAHEDRON | 2017年 / 73卷 / 16期

关键词：

Dolastatin; 10; analogues; Auristatins; N-Terminal modification; Stereoselective synthesis; Dap and Dil; PHASE-II TRIAL; STEREOSELECTIVE-SYNTHESIS; ANTINEOPLASTIC AGENTS; ANTITUMOR-ACTIVITY; BOC-DOLAPROINE; AURISTATIN; POTENT; DIASTEREOISOMERS; DOLAISOLEUINE; CONJUGATE;

D O I：

10.1016/j.tet.2017.03.006

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

We have described the synthesis of the two complex units (2R,3R,4S)-dolaproine (Dap) and (3R,4S,5S)-dolaisoleuine (Dil) of dolastatin 10 from natural amino acids. The stereoselective syntheses of N-Boc-Dap (4a) and N-Boc-(2S)-iso-Dap (4b) were performed by employing crotylation of N-Boc-L-prolinal as a key step. Barbier-type allylation of N-Boc-L-isoleucinal provided a mild and convenient approach for the synthesis of N-Boc-Dil (5a) and N-Boc-(3S)-iso-Dil (5b). Ten dolastatin 10 analogues have been designed and synthesized with N-terminal modifications based on the known compound monomethylauristatin F (MMAF, 3). In comparison with MMAF (3), four of the compounds showed enhanced potency against HCT 116 human colon cancer cells in vitro. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：2255 / 2266

页数：12

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