Design, Synthesis, and Biological Evaluation of Indenoisoquinoline Topoisomerase I Inhibitors Featuring Polyamine Side Chains on the Lactam Nitrogen

Muthukaman Nagarajan, Xiangshu Xiao, Smitha Antony, Glenda Kohlhagen, Yves Pommier, Mark Cushman

Research output: Contribution to journalArticle

127 Scopus citations

Abstract

The indenoisoquinolines are a class of noncamptothecin topoisomerase I inhibitors that display significant cytotoxicity in human cancer cell cultures. They offer a number of potential advantages over the camptothecins, including greater chemical stability, formation of more persistent cleavage complexes, and induction of a unique pattern of DNA cleavage sites. Molecular modeling has suggested that substituents on the indenoisoquinoline lactam nitrogen would protrude out of the DNA duplex in the ternary cleavage complex through the major groove. This indicates that relatively large substituents in that location would be tolerated without compromising biological activity. As a strategy for increasing the potencies and potential therapeutic usefulness of the indenoisoquinolines, a series of compounds was synthesized containing polyamine side chains on the lactam nitrogen. The rationale for the synthesis of these compounds was that the positively charged ammonium cations would increase DNA affinity through electrostatic binding to the negatively charged DNA backbone, and the polyamines might also facilitate cellular uptake by utilization of polyamine transporters. The key step in the synthesis involved the condensation of Schiff bases, containing protected amine side chains, with substituted homophthalic anhydrides, to afford cis-3-aryl-4-carboxy-1-isoquinolones. These isoquinolones were then converted to indenoisoquinolines with thionyl chloride. Although monoamines were much more potent than the lead compound, no significant increase in potency was observed through incorporation of additional amino groups in the side chain. However, one of the monoamine analogues, which features a bis(2-hydroxyethyl)amino group in the side chain, proved to be one of the most cytotoxic indenoisoquinoline synthesized to date, with a GI50 mean-graph midpoint (MGM) of 0.07 μM in the NIH human cancer cell culture screen, and topoisomerase I inhibitory activity comparable to that of camptothecin.

Original languageEnglish (US)
Pages (from-to)5712-5724
Number of pages13
JournalJournal of Medicinal Chemistry
Volume46
Issue number26
DOIs
StatePublished - Dec 18 2003

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this