Positioning of the carboxamide side chain in 11-oxo-11H-indeno[1,2-b]quinolinecarboxamide anticancer agents: Effects on cytotoxicity

A series of 11-oxo-11H-indeno[1,2-b]quinolines bearing a carboxamide-linked cationic side chain at various positions on the chromophore was studied to determine structure-activity relationships between cytotoxicity and the po sition of the side chain. The compounds were prepared by Pfitzinger synthes is from an appropriate isatin and 1-indanone, followed by various oxidative steps, to generate the required carboxylic acids. The 4- and 6-carboxamide s (with the side chain on a terminal ring, off the short axis of the chromo phore) were effective cytotoxins. The dimeric 4- and 6-linked analogues wer e considerably more cytotoxic than the parent monomers, but had broadly sim ilar activities. In contrast, analogues with side chains at the 8-position ton a terminal ring but off the long axis of the chromophore) or 10-positio n (off the short axis of the chromophore but in a central ring) were drasti cally less effective. The 4,10- and 6,10-biscarboxamides had activities bet ween those of the corresponding parent monocarboxamides. The first of these showed good activity against advanced subcutaneous colon 38 tumours in mic e. (C) 2001 Elsevier Science Ltd. All rights reserved.