Work

Synthesis and Biological Evaluation of Nitrated 7-, 8-, 9-, and 10-Hydroxyindenoisoquinolines as Potential Dual Topoisomerase I (Top1)–Tyrosyl-DNA Phosphodiesterase I (TDP1) Inhibitors

Year: 2015

Type: article

Abstract: The structure-activity relationships and hit-to-lead optimization of dual Top1-TDP1 inhibitors in the indenoisoquinoline drug class were investigated. A series of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines were synthesized and evaluated. Several compounds displayed potent dual Top1-TDP1 inhibition. The 9-hydroxy series exhibited potencies and cytotoxicities vs Top1 that surpassed those of camptothecin (CPT), the natural alkaloid that is being used as a standard in the Top1-mediated DNA cleavage assay. One member of this series was a more potent Top1 inhibitor at a concentration of 5 nM and produced a more stable ternary drug-DNA-Top1 cleavage complex than CPT.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.5b00136

Authors: Trung Xuan Nguyen, Monica Abdelmalak, Christophe Marchand, Keli Agama, Yves Pommier, Mark Cushman

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

SDG: Good health and well-being

Open Access status: green

Funders: Purdue Research Foundation, National Institutes of Health, National Cancer Institute