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.

中文翻译：

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具有N末端修饰的dolastatin 10类似物的合成和生物活性评估

我们已经描述了由天然氨基酸合成dolastatin 10的两个复杂单元（2R，3R，4S）-dolaproine（Dap）和（3R，4S，5S）-dolaisoleuine（Dil）的方法。N-Boc-Dap（4a）和N-Boc-（2S）-iso-Dap（4b）的立体选择性合成是通过将N-Boc-1-脯氨酸的crotylation作为关键步骤进行的。N-Boc-1-异亮氨酸的Barbier型烯丙基化为合成N-Boc-Dil（5a）和N-Boc-（3S）-iso-Dil（5b）提供了一种温和而方便的方法。基于已知的化合物单甲基auristatin F（MMAF，3），已经设计并合成了具有N末端修饰的十个dolastatin 10类似物。与MMAF（3）相比，其中四种化合物在体外显示出针对HCT 116人结肠癌细胞的增强效力。