title: 4-Alkylated Silver-N-Heterocyclic Carbene (NHC) Complexes with Cytotoxic Effects in Leukemia Cells.
abstract: Computational chemistry has shown that backbone-alkylated imidazoles ought to be efficient ligands for transition metal catalysts with improved carbene-to-metal donation. In this work, such alkylated imidazoles were synthesized and complexed with silver(I) by means of an eight/nine-step synthetic pathway we devised to access a new class of biologically active silver complexes. The synthesis involves selective iodination of the imidazole backbone, followed by Sonogashira coupling to replace the backbone iodine. The installed alkyne moiety is then subjected to reductive hydrogenation with Pearlman's catalyst. The imidazole N1 atom is arylated by the palladium-catalyzed Buchwald N-arylation method. The imidazole N3 position was then methylated with methyl iodine, whereupon the synthesis was terminated by complexation of the imidazolium salt with silver(I) oxide. The synthetic pathway provided an overall yield of ≈20 %. The resulting complexes were tested in vitro against HL60 and MOLM-13 leukemic cells, two human-derived cell lines that model acute myeloid leukemia. The most active compounds exhibiting low IC50 values of 14 and 27 μM, against HL60 and MOLM-13 cells, respectively. The imidazole side chain was found to be essential for high cytotoxicity, as the imidazole complex bearing a C7 side chain at the 4-position was four- to sixfold more potent than the corresponding imidazole elaborated with a methyl group.
authors.affiliation: Department of Chemistry, University of Bergen, Allégaten 41, 5007 Bergen (Norway).
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Sandtorv
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, 5020 Bergen (Norway).
authors.forename: Calum
authors.initials: C
authors.lastname: Leitch
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, 5020 Bergen (Norway).
authors.forename: Siv Lise
authors.initials: SL
authors.lastname: Bedringaas
authors.affiliation: Center for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, 5020 Bergen (Norway).|Department of Internal Medicine, Hematology Section, Haukeland University Hospital, P.B. 1400, 5021 Bergen (Norway).
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.affiliation: Department of Chemistry, University of Bergen, Allégaten 41, 5007 Bergen (Norway). hans.bjorsvik@kj.uib.no.
authors.forename: Hans-René
authors.initials: HR
authors.lastname: Bjørsvik
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D018922:HL-60 Cells / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D008697:Methane / Q000031:analogs & derivatives / Q000737:chemistry; D012834:Silver / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D007093:Imidazoles; C030011:carbene; D012834:Silver; C029899:imidazole; D008697:Methane
keywords: cytotoxicity; imidazoles; leukemia; metallodrugs; silver