Chemistry of ecteinascidins. Part 4: preparation of 2'-N-acyl ecteinascidin 770 derivatives with improved cytotoxicity profiles.

We report herein eleven 2'-N-acyl derivatives that were prepared from ecteinascidin 770 (Et 770: 1b) via 18,6'-O-bisallyl protected compound (4) in excellent yields. 2'-N-Acyl derivatives (6a-k) generally showed higher cytotoxicity than 1b. Among them, 3-quinolineacyl derivative (6g) and 4-fluorocinnamoyl derivative (6h) exhibited approximately 50- and 70-fold higher cytotoxicity to the HCT116 human colon carcinoma cell line, respectively, than 1b.

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

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.