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. In contrast, the 18,6′-O-bisallyl protected derivatives 4a–c, 6a–h, and 8a–b showed dramatic decreases in cytotoxicity relative to 1b.

Synthesis of 2′-N-amide analogues of ecteinascidin 770 (Et 770) via a three-step transformation employing an 18,6′-O-bisallyl protected derivative of Et 770 is presented along with in vitro cytotoxicity of the resulting amides.Figure optionsDownload as PowerPoint slide