Synthesis and biological evaluation of bisindenoisoquinolines as topoisomerase I inhibitors

Muthukaman, N, Morrell, A, Smitha, A, Kohlhagen, G, Agama, K, Pommier, Y, Ragazzon, PA, Garbett, N, Chaires, J, Hollingshead, M and Cushman, M 2006, 'Synthesis and biological evaluation of bisindenoisoquinolines as topoisomerase I inhibitors' , Journal of Medicinal Chemistry, 24 (49) , pp. 5129-5140.

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The indenoisoquinolines represent a class of non-camptothecin topoisomerase I (Top1) inhibitors that exert cytotoxicity by trapping the covalent complex formed between DNA and Top1 during relaxation of DNA supercoils. As an ongoing evaluation of Top1 inhibition and anticancer activity, indenoisoquinolines were linked via their lactam side chains to provide polyamines end-capped with intercalating motifs. The resulting bisindenoisoquinolines were evaluated for cytotoxicity in the National Cancer Institute's human cancer cell screen and for Top1 inhibition. Preliminary findings suggested that the 2-3-2 and 3-3-3 linkers, referring to the number of carbons between nitrogen atoms, were optimal for both potent Top1 inhibition and cytotoxicity. Using optimized linkers, bisindenoisoquinolines were synthesized with nitro and methoxy substituents on the aromatic rings. The biological results for substituted compounds revealed a disagreement between the structure-activity relationships of monomeric indenoisoquinolines and bisindenoisoquinolines as Top1 inhibitors, but cytotoxicity was maintained for both series of compounds.

Item Type: Article
Themes: Health and Wellbeing
Schools: Schools > School of Environment and Life Sciences > Biomedical Research Centre
Journal or Publication Title: Journal of Medicinal Chemistry
Publisher: ACS Publications
Refereed: Yes
ISSN: 0022-2623
Related URLs:
Funders: NIH Research Grant, NIH Training Grant, NIH Developmental Therapeutics Program,
Depositing User: PA Ragazzon
Date Deposited: 26 Jan 2015 14:03
Last Modified: 16 Feb 2022 16:04

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