title: Iminolactones as tools for inversion of the absolute configuration of α-amino acids and as inhibitors of cancer cell proliferation.
abstract: A library of iminolactones was prepared by esterification of several 2-hydroxyketones with a number of N-protected d- and l-α-amino acids. Some of the hydroxyketones were of terpenoid origin while others were obtained via synthesis. After N-deprotection of the intermediate esters, the free amines spontaneously underwent condensation with the ketone to form iminolactones. Esters of (1S,2S,5S)-2-hydroxypinan-3-one with both d- and l-α-amino acids were partially epimerized at the α-carbon atom to give a diastereomeric ester mixture. Only iminolactones of l-amino acids were formed after cyclization of (1S,2S,5S)-2-hydroxypinan-3-one, and correspondingly only d-amino acid iminolactones were formed after reaction with (1R,2R,5R)-2-hydroxypinan-3-one. The protocol thus enables inversion of the absolute configuration of amino acids. Some members of the prepared library of iminolactones displayed significant anti-proliferative effects toward three cancer cell lines (EL4, MCF7, PC3) with insignificant effect on non-malign cell lines (McCoy, MCF10A, NIH3T3). Thus, iminolactones appear to be potential lead structures for preparation of drugs selectively affecting proliferation of malign cell lines.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Christina Mernøe
authors.initials: CM
authors.lastname: Jensen
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Hsiao-Qing
authors.initials: HQ
authors.lastname: Chow
authors.affiliation: Department of Clinical Microbiology 7602, Rigshospitalet, Tagensvej 20, DK-2200 Copenhagen N, Denmark.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhai
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Huizhen
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Franzyk
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark. Electronic address: soren.christensen@sund.ku.dk.
authors.forename: Søren Brøgger
authors.initials: SB
authors.lastname: Christensen
mesh_terms: D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000473:pathology*; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D007783:Lactones
keywords: Anti-proliferative effects; Iminolactones; Inversion of amino acids; JNUXNNIJITXLIQ-IZHRTLMJSA-N; Selective inhibition