Optimization of the Indenone Ring of Indenoisoquinoline Topoisomerase I Inhibitors

Two series of indenoisoquinoline topoisomerase I inhibitors have been prepared to investigate optimal substituents on the indenone ring at the 9-position. The more exhaustive series was prepared using a nitrated isoquinoline ring that has been previously demonstrated to enhance biological activity....

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-09, Vol.50 (18), p.4388-4404
Main Authors: Morrell, Andrew, Placzek, Michael, Parmley, Seth, Grella, Brian, Antony, Smitha, Pommier, Yves, Cushman, Mark
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Line, Tumor
Crystallography, X-Ray
DNA Cleavage - drug effects
DNA Topoisomerases, Type I - chemistry
Drug Screening Assays, Antitumor
General aspects
Humans
Indenes - chemical synthesis
Indenes - chemistry
Indenes - pharmacology
Isoquinolines - chemical synthesis
Isoquinolines - chemistry
Isoquinolines - pharmacology
Medical sciences
Models, Molecular
Molecular Structure
Pharmacology. Drug treatments
Structure-Activity Relationship
Topoisomerase I Inhibitors
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Summary:Two series of indenoisoquinoline topoisomerase I inhibitors have been prepared to investigate optimal substituents on the indenone ring at the 9-position. The more exhaustive series was prepared using a nitrated isoquinoline ring that has been previously demonstrated to enhance biological activity. After preliminary biological evaluation, a more focused series of inhibitors was prepared utilizing a 2,3-dimethoxy-substituted isoquinoline ring. The results of the two series indicate the existence of superior functional groups such as methoxy, fluorine, and cyano for the indenoisoquinoline 9-position. Interestingly, these functional groups coincide with established structure−activity relationships for the 11-position of camptothecin.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm070307+