title: Synthesis and biological evaluation of new fluorinated and chlorinated indenoisoquinoline topoisomerase I poisons.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Beck
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Lv
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 21892, United States.
authors.forename: Monica
authors.initials: M
authors.lastname: Abdelmalak
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 21892, United States.
authors.forename: Caroline B
authors.initials: CB
authors.lastname: Plescia
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 21892, United States.
authors.forename: Keli
authors.initials: K
authors.lastname: Agama
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 21892, United States.
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 21892, United States.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States. Electronic address: cushman@purdue.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007192:Indenes; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I
keywords: Anticancer; Cytotoxicity; Indenoisoquinoline; Topoisomerase I; Tyrosyl DNA phosphodiesterase 1; Tyrosyl DNA phosphodiesterase 2