报道了细胞毒性天然产物微管溶素 U、微管溶素 V 及其非天然差向异构体表观微管溶素 V 的立体选择性全合成。含简化类似物Ñ,Ñ二甲基d丙氨酸作为N-末端的替代Ñ微管溶素的-Me-2-哌啶酸残基也被公开。这些天然产物和类似物的生物学评价提供了关于抗增殖活性和微管蛋白聚合抑制的结构和立体化学要求的关键信息。
Tubulysin analogs incorporating desmethyl and dimethyl tubuphenylalanine derivatives
摘要:
A series of tubulysin analogs in which one of the stereogenic centers of tubuphenylalanine was eliminated were synthesized. All compounds were tested for antiproliferative activity towards ovarian cancer cells and for inhibition of tubulin polymerization. The dimethyl analogs were generally more active than the desmethyl analogs, and four analogs have tubulin polymerization IC50 values similar to combretastatin A4 and the hemiasterlin analog HTI-286. (C) 2008 Elsevier Ltd. All rights reserved.