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Guanidinium-based derivatives : searching for new kinase inhibitors

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dc.contributor.authorDiez Cecilia, E.
dc.contributor.authorKelly, B.
dc.contributor.authorPerez, C.
dc.contributor.authorZisterer, D.M.
dc.contributor.authorNevin, D.K.
dc.contributor.authorLloyd, D.G.
dc.contributor.authorRozas, I.
dc.date.issued2014
dc.description.abstractConsidering the structural similarities between the kinase inhibitor sorafenib and 4,40-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 3,40-bis-guanidiniums, 3,40-bis-2- aminoimidazolinium and 3-acetamide-40-(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 4,40-bis-guanidiniums did not inhibit any of these kinases; however, some of the novel 3,40-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.
dc.identifier.citationEuropean Journal of Medicinal Chemistry, 2014; 81:427-441
dc.identifier.doi10.1016/j.ejmech.2014.05.025
dc.identifier.issn0223-5234
dc.identifier.issn1768-3254
dc.identifier.urihttps://hdl.handle.net/1959.8/158379
dc.language.isoen
dc.publisherElsevier
dc.relation.fundingHEA-PRTL-4 (B.K.)
dc.relation.fundingIRC (E.D.C.)
dc.rightsCopyright 2014 Elsevier Masson SAS Access Condition Notes: Postprint available 23 June 2016
dc.source.urihttps://doi.org/10.1016/j.ejmech.2014.05.025
dc.subjectdocking
dc.subjectguanidine
dc.subjectMEK-1
dc.subjectprotein kinases
dc.subjectRAF-1
dc.subjectsorafenib
dc.titleGuanidinium-based derivatives : searching for new kinase inhibitors
dc.typeJournal article
pubs.publication-statusPublished
ror.fileinfo12142884060001831 13142967360001831 9915914131101831_53109904900001831.pdf
ror.mmsid9915914131101831

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