title: One-Step Synthetic Access to Isosteric and Potent Anticancer Nitrogen Heterocycles with the Benzo[c]phenanthridine Scaffold.
abstract: A versatile one-step two-component cyclization to build new tetracyclic nitrogen heterocycles is described. Ortho-methylhetarenecarbonitrile components were condensed with aldehydes to access a large library of differently substituted ring systems. The heterocyclic core can be easily modified by variation of the position of the endocyclic nitrogen atom in the o-methylhetarenecarbonitrile substrate. The manner of the nucleophilic attack that leads to the condensation can be triggered by different electron-density distribution in the molecule induced by the position of the nitrogen atom. Taking this into account, there is an electronic preference that leads to either pyridophenanthrolines or the corresponding pyridoazacarbazoles as the main products. We demonstrate the high antitumor potential of some of our synthesized heterocycles, which is strongly dependent on the substitution pattern introduced through the aldehyde component. The position and number of endocyclic nitrogen atoms play an important role regarding cytotoxicity of the studied compounds.
authors.affiliation: Pharmazeutisches Institut, Lehrstuhl für Pharmazeutische Chemie, Universität Kiel, Gutenbergstrasse 76, 24118, Kiel, Germany), Fax.
authors.forename: Tamara N
authors.initials: TN
authors.lastname: Steinhauer
authors.affiliation: Pharmazeutisches Institut, Lehrstuhl für Pharmazeutische Chemie, Universität Kiel, Gutenbergstrasse 76, 24118, Kiel, Germany), Fax.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Girreser
authors.affiliation: Pharmazeutisches Institut, Lehrstuhl für Pharmazeutische Chemie, Universität Kiel, Gutenbergstrasse 76, 24118, Kiel, Germany), Fax.
authors.forename: Christopher
authors.initials: C
authors.lastname: Meier
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy and, The Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana, 47907, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.affiliation: Pharmazeutisches Institut, Lehrstuhl für Pharmazeutische Chemie, Universität Kiel, Gutenbergstrasse 76, 24118, Kiel, Germany), Fax. bclement@pharmazie.uni-kiel.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Clement
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D009584:Nitrogen / Q000737:chemistry; D010617:Phenanthridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D010617:Phenanthridines; C000620893:benzo(c)phenanthridine; D009584:Nitrogen
keywords: antitumor agents; fused-ring systems; medicinal chemistry; nitrogen heterocycles; synthetic methods