海兔毒素的化学。第 3 部分：海兔毒素 770 的 2'-N-酰基衍生物的制备及细胞毒性评价。

Chemistry of ecteinascidins. Part 3: preparation of 2'-N-acyl derivatives of ecteinascidin 770 and evaluation of cytotoxicity.

机构信息

Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand.

出版信息

Bioorg Med Chem. 2011 Aug 1;19(15):4421-36. doi: 10.1016/j.bmc.2011.06.047. Epub 2011 Jun 21.

DOI:10.1016/j.bmc.2011.06.047

PMID:21752654

Abstract

A three-step transformation of ecteinascidin 770 (1b) into 2'-N-indole-3-carbonyl derivative 3 via 18,6'-O-bisallyl-protected derivative 4a, which was shown to have higher cytotoxicity than 1b, is presented. In addition, a number of 2'-N amide derivatives of 1b have been prepared from 4a and their in vitro cytotoxicity were determined by measuring IC₅₀ values against human cell lines HCT116, QG56, and DU145. Benzoyl amide derivatives 7a-c showed similar in vitro cytotoxicity to 1b, whereas the nitrogen-containing heterocyclic derivatives 7d-h and cinnamoyl derivatives 9a-b showed higher cytotoxicity than 1b. In contrast, the 18,6'-O-bisallyl protected derivatives 4a-c, 6a-h, and 8a-b showed dramatic decreases in cytotoxicity relative to 1b.

摘要

本文报道了依托泊苷 770（1b）经三步转化为 2′-N-吲哚-3-甲酰基衍生物 3 的过程，其中 18,6′-O-双烯丙基保护的衍生物 4a 显示出比 1b 更高的细胞毒性。此外，还从 4a 制备了一系列 1b 的 2′-N 酰胺衍生物，并通过测定其对 HCT116、QG56 和 DU145 人细胞系的 IC₅₀ 值来确定其体外细胞毒性。苯甲酰酰胺衍生物 7a-c 显示出与 1b 相似的体外细胞毒性，而含氮杂环衍生物 7d-h 和肉桂酰衍生物 9a-b 则显示出比 1b 更高的细胞毒性。相比之下，18,6′-O-双烯丙基保护的衍生物 4a-c、6a-h 和 8a-b 的细胞毒性相对于 1b 显著降低。