title: Synthesis and functional survey of new Tacrine analogs modified with nitroxides or their precursors.
abstract: A series of new Tacrine analogs modified with nitroxides or pre-nitroxides on 9-amino group via methylene or piperazine spacers were synthesized; the nitroxide or its precursors were incorporated into the Tacrine scaffold. The new compounds were tested for their hydroxyl radical and peroxyl radical scavenging ability, acetylcholinesterase inhibitor activity and protection against Aβ-induced cytotoxicity. Based on these assays, we conclude that Tacrine analogs connected to five and six-membered nitroxides via piperazine spacers (9b, 9b/HCl and 12) exhibited the best activity, providing direction for further development of additional candidates with dual functionality (anti Alzheimer's and antioxidant).
authors.affiliation: Institute of Organic and Medicinal Chemistry, University of Pécs, H-7624 Pécs, Szigeti St. 12. Pécs, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Kálai
authors.affiliation: Department of Biochemistry & Molecular Medicine, University of California Davis, Davis, CA 95616, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Altman
authors.affiliation: M.I.N.D. Institute and Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA95817, USA.
authors.forename: Izumi
authors.initials: I
authors.lastname: Maezawa
authors.affiliation: Institute of Organic and Medicinal Chemistry, University of Pécs, H-7624 Pécs, Szigeti St. 12. Pécs, Hungary.
authors.forename: Mária
authors.initials: M
authors.lastname: Balog
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: Department of Biochemistry & Molecular Medicine, University of California Davis, Davis, CA 95616, USA.
authors.forename: Jitka
authors.initials: J
authors.lastname: Petrlova
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: M.I.N.D. Institute and Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA95817, USA.
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
authors.affiliation: Department of Anesthesia, Beckman Program for Molecular and Genetic Medicine, Stanford University, Stanford, CA 94305-5117, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Trudell
authors.affiliation: Department of Biochemistry & Molecular Medicine, University of California Davis, Davis, CA 95616, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Voss
authors.affiliation: Institute of Organic and Medicinal Chemistry, University of Pécs, H-7624 Pécs, Szigeti St. 12. Pécs, Hungary. Electronic address: kalman.hideg@aok.pte.hu.
authors.forename: Kálmán
authors.initials: K
authors.lastname: Hideg
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009589:Nitrogen Oxides / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D009589:Nitrogen Oxides; D013619:Tacrine; D000110:Acetylcholinesterase
keywords: Alzheimer's disease; Antioxidants; Nitroxides; Spin trapping; Tacrine