title: Guanidinium-based derivatives: searching for new kinase inhibitors.
abstract: Considering the structural similarities between the kinase inhibitor sorafenib and 4,4'-bis-guanidinium derivatives previously prepared by Rozas and co., which display interesting cytotoxicity in cancer cells, we have studied whether this activity could result from kinase inhibition. Five new families have been prepared consisting of unsubstituted and aryl-substituted 3,4'-bis-guanidiniums, 3,4'-bis-2-aminoimidazolinium and 3-acetamide-4'-(4-chloro-3-trifluoromethylphenyl)guanidinium derivatives. Cytotoxicity (measuring the IC50 values) and apoptosis studies in human HL-60 promyelocytic leukemia cells were carried out for these compounds. Additionally, their potential inhibitory effect was explored on a panel of kinases known to be involved in apoptotic pathways. The previously prepared cytotoxic 4,4'-bis-guanidiniums did not inhibit any of these kinases; however, some of the novel 3,4'-substituted derivatives showed a high percentage inhibition of RAF-1/MEK-1, for which the potential mode of binding was evaluated by docking studies. The interesting antitumour properties showed by these compounds open up new exciting lines of investigation for kinase inhibitors as anticancer agents and also highlights the relevance of the guanidinium moiety for protein kinase inhibitors chemical design.
authors.affiliation: School of Chemistry, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, 154-160 Pearse St., Dublin 2, Ireland.
authors.forename: Elena
authors.initials: E
authors.lastname: Diez-Cecilia
authors.affiliation: School of Chemistry, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, 154-160 Pearse St., Dublin 2, Ireland.
authors.forename: Brendan
authors.initials: B
authors.lastname: Kelly
authors.affiliation: Instituto de Qumica Medica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Concepcion
authors.initials: C
authors.lastname: Perez
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 154-160 Pearse St., Dublin 2, Ireland.
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 154-160 Pearse St., Dublin 2, Ireland.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nevin
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 154-160 Pearse St., Dublin 2, Ireland.
authors.forename: David G
authors.initials: DG
authors.lastname: Lloyd
authors.affiliation: School of Chemistry, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, 154-160 Pearse St., Dublin 2, Ireland. Electronic address: rozasi@tcd.ie.
authors.forename: Isabel
authors.initials: I
authors.lastname: Rozas
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D019791:Guanidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010770:Phosphotransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D047428:Protein Kinase Inhibitors; D010770:Phosphotransferases; D040262:Receptors, Vascular Endothelial Growth Factor; D019791:Guanidine
keywords: Docking; Guanidine; MEK-1; Protein kinases; RAF-1; Sorafenib