1. Guanidinium-based derivatives: Searching for new kinase inhibitors
- Author
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Elena Diez-Cecilia, Isabel Rozas, Daniela M. Zisterer, Concepción Pérez, Brendan Kelly, David Lloyd, Daniel K. Nevin, Diez-Cecilia, E, Kelly, B, Perez, c, Zisterer, D M, Nevin, D K, Lloyd, David George, and Rozas, Isabel
- Subjects
MAPK/ERK pathway ,Models, Molecular ,Stereochemistry ,Cell Survival ,Antineoplastic Agents ,Apoptosis ,HL-60 Cells ,guanidine ,chemistry.chemical_compound ,Structure-Activity Relationship ,Protein kinases ,Cell Line, Tumor ,Drug Discovery ,Human Umbilical Vein Endothelial Cells ,Organometallic Compounds ,Humans ,Guanidine ,Cytotoxicity ,Protein kinase A ,Protein Kinase Inhibitors ,Cell Proliferation ,Pharmacology ,protein kinases ,RAF-1 ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Kinase ,MEK-1 ,Organic Chemistry ,Phosphotransferases ,General Medicine ,Sorafenib ,Receptors, Vascular Endothelial Growth Factor ,chemistry ,Biochemistry ,Docking (molecular) ,docking ,Cancer cell ,biology.protein ,sorafenib ,Drug Screening Assays, Antitumor ,Platelet-derived growth factor receptor - 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. © 2014 Elsevier Masson SAS. All rights reserved.
- Published
- 2014