Format

Send to

Choose Destination
See comment in PubMed Commons below
Eur J Med Chem. 2014 Jun 23;81:427-41. doi: 10.1016/j.ejmech.2014.05.025. Epub 2014 May 9.

Guanidinium-based derivatives: searching for new kinase inhibitors.

Author information

1
School of Chemistry, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, 154-160 Pearse St., Dublin 2, Ireland.
2
Instituto de Qumica Medica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
3
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 154-160 Pearse St., Dublin 2, Ireland.
4
School of Chemistry, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, 154-160 Pearse St., Dublin 2, Ireland. Electronic address: rozasi@tcd.ie.

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.

KEYWORDS:

Docking; Guanidine; MEK-1; Protein kinases; RAF-1; Sorafenib

PMID:
24858546
DOI:
10.1016/j.ejmech.2014.05.025
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Support Center