Discovery of potent indenoisoquinoline topoisomerase I poisons lacking the 3-nitro toxicophore.
作者： Daniel E Beck , Monica Abdelmalak , Wei Lv , PV Narasimha Reddy , Gabrielle S Tender
DOI: 10.1021/ACS.JMEDCHEM.5B00303
关键词: Cytotoxicity 、 Topoisomerase 、 Dna cleavage 、 Nitro 、 Toxicophore 、 Chemistry 、 Stereochemistry 、 Cancer cell 、 Cell culture 、 Pharmacology
摘要: 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. molecules evaluated in Top1-mediated DNA cleavage assay National Cancer Institute’s 60 cell line cytotoxicity assay. data reveal fluorine chlorine may substitute for group with minimal loss Top1 poisoning activity. new information gained from these efforts can used to design novel improved safety.
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