2. Academic Validation
  3. Discovery of potent indenoisoquinoline topoisomerase I poisons lacking the 3-nitro toxicophore

Discovery of potent indenoisoquinoline topoisomerase I poisons lacking the 3-nitro toxicophore

  • J Med Chem. 2015 May 14;58(9):3997-4015. doi: 10.1021/acs.jmedchem.5b00303.
Daniel E Beck 1,  Monica Abdelmalak 2,  Wei Lv 1,  P V Narasimha Reddy 1,  Gabrielle S Tender 2,  Elizaveta O'Neill 1,  Keli Agama 2,  Christophe Marchand 2,  Yves Pommier 2,  Mark Cushman 1
Affiliations

Affiliations

  • 1 †Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
  • 2 ‡Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NCI-Frederick, Frederick, Maryland 21702, United States.
PMID: 25909279 DOI: 10.1021/acs.jmedchem.5b00303
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.

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