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 position of the side chain. The compounds were prepared by Pfitzinger synthesis from an appropriate isatin and 1-indanone, followed by various oxidative steps, to generate the required carboxylic acids. The 4- and 6-carboxamides (with the side chain on a terminal ring, off the short axis of the chromophore) were effective cytotoxins. The dimeric 4- and 6-linked analogues were considerably more cytotoxic than the parent monomers, but had broadly similar activities. In contrast, analogues with side chains at the 8-position (on a terminal ring but off the long axis of the chromophore) or 10-position (off the short axis of the chromophore but in a central ring) were drastically less effective. The 4,10- and 6,10-biscarboxamides had activities between those of the corresponding parent monocarboxamides. The first of these showed good activity against advanced subcutaneous colon 38 tumours in mice.
Department of Chemistry, La Trobe University, Bundoora, Victoria, Australia. L.Deady@latrobe.edu.au
L W
LW
Deady
J
J
Desneves
A J
AJ
Kaye
G J
GJ
Finlay
B C
BC
Baguley
W A
WA
Denny
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
C431771:11-oxo-11H-indeno(1,2-b)quinolinecarboxamide; D000577:Amides; D000970:Antineoplastic Agents; D007192:Indenes; D011804:Quinolines