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 synthes...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2001-02, Vol.9 (2), p.445-452
Main Authors: DEADY, Leslie W, DESNEVES, José, KAYE, Anthony J, FINLAY, Graeme J, BAGULEY, Bruce C, DENNY, William A
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - pharmacology
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Biological and medical sciences
Carcinoma, Lewis Lung - pathology
Cell Division - drug effects
Chemotherapy
Colonic Neoplasms - drug therapy
Combinatorial Chemistry Techniques
Humans
Indenes - chemical synthesis
Indenes - pharmacology
Inhibitory Concentration 50
Leukemia - pathology
Medical sciences
Mice
Neoplasm Transplantation
Pharmacology. Drug treatments
Quinolines - chemical synthesis
Quinolines - pharmacology
Structure-Activity Relationship
Tumor Cells, Cultured - drug effects
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Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(00)00264-9