Synthesis and Biological Evaluation of Bisindenoisoquinolines as Topoisomerase I Inhibitors

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• 作者：Muthukaman Nagarajan ; Andrew Morrell ; Smitha Antony ; Glenda Kohlhagen ; Keli Agama ; Yves Pommier ; Patricia A. Ragazzon ; Nichola C. Garbett ; Jonathan B. Chaires ; Melinda Hollingshead ; Mark Cushman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：August 24, 2006
• 年：2006
• 卷：49
• 期：17
• 页码：5129 - 5140
• 全文大小：355K
• 年卷期：v.49,no.17(August 24, 2006)
• ISSN：1520-4804

文摘

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