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

doi:10.1021/acs.jmedchem.5b00303

Paper

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

Published Apr 24, 2015 · DOI · D. Beck, Monica Abdelmalak, Wei-Ke Lv

Journal of medicinal chemistry

40

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1

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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.

In Vitro Study

Study Snapshot

Fluorine and chlorine can replace the 3-nitro toxicophore in indenoisoquinolines, retaining their antiproliferative effects on cancer cells while minimizing safety risks.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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

References

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