title: 11-Substituted Benzo[c]phenanthridines: New Structures and Insight into Their Mode of Antiproliferative Action.
abstract: The synthesis of various new structures of a library of 11-substituted 6-amino-11,12-dihydrobenzo[c]phenanthridines (BP) and 11-substituted 6-aminobenzo[c]phenanthridines (BP-D) is presented. These structures, further synthetic modifications, and the preparation of follow-up products which delivered about 40 new derivatives are described. Their potential as antiproliferative drug candidates was investigated by comparison of NCI 60 developmental therapeutics program (DTP) human tumor cell line screening data based on the results of in vitro tumor cell growth inhibition, including about 40 hitherto unpublished compound test results with up to 60 cancer cell lines. NCI-COMPARE studies helped to suggest the modes of action of the highly active antiproliferative drugs. These findings are supported by in vitro biological investigations showing either inhibition of tubulin polymerization and depolymerization or topoisomerase inhibition. Together with physicochemical parameters of the drug candidates, structure-activity relationships are critically discussed. Tubulin interaction or inhibition of topoisomerase I and IIα/β activity are two rationales that can explain the antiproliferative activity observed in the NCI 60 DTP human tumor cell line screen. However, it can also be reasonably assumed that these compounds address several targets, thus prohibiting the identification of simple structure-activity relationships. The new structures described herein are thought to act as so-called multitarget drugs, thus being of special interest in the area of multidrug resistance.
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Pharmaceutical, Institute, Gutenbergstr. 76, 24118, Kiel, Germany. bclement@pharmazie.uni-kiel.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Clement
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Pharmaceutical, Institute, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Girreser
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Pharmaceutical, Institute, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Tamara N
authors.initials: TN
authors.lastname: Steinhauer
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Pharmaceutical, Institute, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Meier
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Waehringer Str. 38, 1090, Vienna, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Marko
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Waehringer Str. 38, 1090, Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Aichinger
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Pharmaceutical, Institute, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Kaltefleiter
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Pharmaceutical, Institute, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Stenzel
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Pharmaceutical, Institute, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Heber
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Pharmaceutical, Institute, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Weide
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Pharmaceutical, Institute, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wolschendorf
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Pharmaceutical, Institute, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Zebothsen
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Pharmaceutical, Institute, Gutenbergstr. 76, 24118, Kiel, Germany.
authors.forename: Dana
authors.initials: D
authors.lastname: Zur Nieden
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D010617:Phenanthridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058105:Polymerization; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D010617:Phenanthridines; D059003:Topoisomerase Inhibitors; D014404:Tubulin; C000620893:benzo(c)phenanthridine; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II
keywords: antiproliferative activity; aza heterocycles; benzo[c]phenanthridines; multitarget drugs