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Discovery of Potent Indenoisoquinoline Topoisomerase I Poisons Lacking the 3-Nitro Toxicophore

Year: 2015
Type: article
Abstract: 3-Nitroindenoisoquinoline human topoisomerase IB (Top1) poisons have potent antiproliferative effects on cancer cells. The undesirable nitro toxicophore could hypothetically be replaced by other functional groups that would retain the desired biological activities and minimize potential safety risks. Eleven series of indenoisoquinolines bearing 3-nitro bioisosteres were synthesized. The molecules were evaluated in the Top1-mediated DNA cleavage assay and in the National Cancer Institute's 60 cell line cytotoxicity assay. The data reveal that fluorine and chlorine may substitute for the 3-nitro group with minimal loss of Top1 poisoning activity. The new information gained from these efforts can be used to design novel indenoisoquinolines with improved safety.
DOI: 10.1021/acs.jmedchem.5b00303
Authors: Daniel E. Beck, Monica Abdelmalak, Wei Lv, P. V. Narasimha Reddy, Gabrielle S. Tender, Elizaveta O’Neill, Keli Agama, Christophe Marchand, Yves Pommier, Mark Cushman
Language: English
Open Access status: green
Awards: G295951168, G3029148, DNA Topoisomerases as Target of Action of Anticancer Drugs, G4093230697, Cancer Center Support Grant, OPERATIONS &TECHNICAL SUPPORT, G9000020722
OpenAlex ID: W2093255751
FWCI: 2.701
Cites: 62
Cited by: 51
Related to: 10