Work

Design, Synthesis, and Evaluation of Dibenzo[c,h][1,6]naphthyridines as Topoisomerase I Inhibitors and Potential Anticancer Agents

Year: 2010

Type: article

Abstract: Indenoisoquinoline topoisomerase I (Top1) inhibitors are a novel class of anticancer agents. Modifications of the indenoisoquinoline A, B, and D rings have been extensively studied in order to optimize Top1 inhibitory activity and cytotoxicity. To improve understanding of the forces that stabilize drug-Top1-DNA ternary complexes, the five-membered cyclopentadienone C-ring of the indenoisoquinoline system was replaced by six-membered nitrogen heterocyclic rings, resulting in dibenzo[c,h][1,6]naphthyridines that were synthesized by a novel route and tested for Top1 inhibition. This resulted in several compounds that have unique DNA cleavage site selectivities and potent antitumor activities in a number of cancer cell lines.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/jm101048k

Authors: Evgeny Kiselev, Thomas S. Dexheimer, Yves Pommier, Mark Cushman

Institutions: Purdue University West Lafayette, National Cancer Institute, Center for Cancer Research

Language: English

Topic: Cancer therapeutics and mechanisms

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: National Science Council, National Institutes of Health, National Cancer Institute

Awards: Novel Indenoisoquinoline Topoisomerase I Inhibitors, G4093230697, G675219647