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

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.

• 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 9 Pg. 3997-4015 (May 14 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 25909279 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Antineoplastic Agents
• Indenes
• Isoquinolines
• Topoisomerase I Inhibitors
• DNA

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Crystallography, X-Ray
• DNA (metabolism)
• Drug Screening Assays, Antitumor
• Humans
• Hydrogen Bonding
• Indenes (chemical synthesis, chemistry, pharmacology)
• Isoquinolines (chemical synthesis, chemistry, pharmacology)
• Molecular Conformation
• Protein Binding
• Quantum Theory
• Stereoisomerism
• Structure-Activity Relationship
• Thermodynamics
• Topoisomerase I Inhibitors (chemical synthesis, chemistry, pharmacology)