Bioorganic & Medicinal Chemistry Letters 2005-01-03

Design, synthesis, and biological evaluation of achiral analogs of duocarmycin SA.

Kristen Daniell, Michelle Stewart, Erik Madsen, Minh Le, Heather Handl, Natalie Brooks, Konstantinos Kiakos, John A Hartley, Moses Lee

Index: Bioorg. Med. Chem. Lett. 15(1) , 177-80, (2005)

Full Text: HTML

Abstract

The design, synthesis, as well as biochemical and biological evaluation of two novel achiral analogs of duocarmycin SA (DUMSA), 1 and 2, are described. Like CC-1065 and adozelesin, compounds 1 and 2 covalently reacted with adenine-N3 in AT-rich sequences and led to the formation of DNA strand breaks upon heating. The cytotoxicity of compounds 1 and 2 against human cancer cells (K562, LS174T) was determined using a MTT assay giving IC(50) values in the low nanomolar. Further cytotoxicity screening of compound 2 conducted by the NCI against a panel of 60 different human cancer cell lines indicated that it was particularly active against several solid tumor cells lines derived from the lung, colon, CNS, skin, and breast.