Open AccessDiscovery of Potent Indenoisoquinoline Topoisomerase I Poisons Lacking the 3-Nitro Toxicophore
Author(s) -
Daniel E. Beck,
Monica Abdelmalak,
Wei Lv,
P. Venkat Reddy,
Gabrielle S. Tender,
Elizaveta O’Neill,
Keli Agama,
Christophe Marchand,
Yves Pommier,
Mary Cushman
Publication year - 2015
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.5b00303
Subject(s) - chemistry , nitro , topoisomerase , cytotoxicity , cleavage (geology) , stereochemistry , combinatorial chemistry , pharmacology , dna , biochemistry , in vitro , organic chemistry , medicine , alkyl , geotechnical engineering , fracture (geology) , engineering
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.