biostudies-literatureBeck DEIntramural NIH HHSNCI NIH HHS1469-79https://www.ebi.ac.uk/biostudies/studies/S-EPMC4789169biostudies-literatureUnknown24(7)Fluorine and chlorine are metabolically stable, but generally less active replacements for a nitro group at the 3-position of indenoisoquinoline topoisomerase IB (Top1) poisons. A number of strategies were employed in the present investigation to enhance the Top1 inhibitory potencies and cancer cell growth inhibitory activities of halogenated indenoisoquinolines. In several cases, the new compounds' activities were found to rival or surpass those of similarly substituted 3-nitroindenoisoquinolines, and several unusually potent analogs were discovered through testing in human cancer cell cultures. A hydroxyethylaminopropyl side chain on the lactam nitrogen of two halogenated indenoisoquinoline Top1 inhibitors was found to also impart inhibitory activity against tyrosyl DNA phosphodiesterases 1 and 2 (TDP1 and TDP2), which are enzymes that participate in the repair of DNA damage induced by Top1 poisons.Bioorganic & medicinal chemistrySynthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons.PMC4789169U01CA089566Z01BC006161P30 CA023168U01 CA089566Z01 BC006161N01-CO-56000P30CA023168Marchand CPommier YCushman MLv WAbdelmalak MPlescia CBAgama KBeck DEfalseSynthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons.Fluorine and chlorine are metabolically stable, but generally less active replacements for a nitro group at the 3-position of indenoisoquinoline topoisomerase IB (Top1) poisons. A number of strategies were employed in the present investigation to enhance the Top1 inhibitory potencies and cancer cell growth inhibitory activities of halogenated indenoisoquinolines. In several cases, the new compounds' activities were found to rival or surpass those of similarly substituted 3-nitroindenoisoquinolines, and several unusually potent analogs were discovered through testing in human cancer cell cultures. A hydroxyethylaminopropyl side chain on the lactam nitrogen of two halogenated indenoisoquinoline Top1 inhibitors was found to also impart inhibitory activity against tyrosyl DNA phosphodiesterases 1 and 2 (TDP1 and TDP2), which are enzymes that participate in the repair of DNA damage induced by Top1 poisons.2016-01-01T00:00:00Z2016 Apr2020-11-19T15:38:07Z2019-03-27T02:10:59ZS-EPMC47891692690647410.1016/j.bmc.2016.02.015