title: 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.affiliation: †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.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Beck
authors.affiliation: ‡Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NCI-Frederick, Frederick, Maryland 21702, United States.
authors.forename: Monica
authors.initials: M
authors.lastname: Abdelmalak
authors.affiliation: †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.
authors.forename: Wei
authors.initials: W
authors.lastname: Lv
authors.affiliation: †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.
authors.forename: P V Narasimha
authors.initials: PV
authors.lastname: Reddy
authors.affiliation: ‡Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NCI-Frederick, Frederick, Maryland 21702, United States.
authors.forename: Gabrielle S
authors.initials: GS
authors.lastname: Tender
authors.affiliation: †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.
authors.forename: Elizaveta
authors.initials: E
authors.lastname: O'Neill
authors.affiliation: ‡Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NCI-Frederick, Frederick, Maryland 21702, United States.
authors.forename: Keli
authors.initials: K
authors.lastname: Agama
authors.affiliation: ‡Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NCI-Frederick, Frederick, Maryland 21702, United States.
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.affiliation: ‡Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NCI-Frederick, Frederick, Maryland 21702, 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, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006860:Hydrogen Bonding; D007192:Indenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008968:Molecular Conformation; D011485:Protein Binding; D011789:Quantum Theory; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007192:Indenes; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors; D004247:DNA