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Diez-Cecilia E.,Trinity College Dublin | Kelly B.,Trinity College Dublin | Perez C.,Institute Qumica Medica CSIC | Zisterer D.M.,Trinity College Dublin | And 3 more authors.
European Journal of Medicinal Chemistry | Year: 2014

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.


Alkorta I.,Institute Qumica Medica CSIC | Elguero J.,Institute Qumica Medica CSIC | Provasi P.F.,Northeastern University | Pagola G.I.,FCEyN | Ferraro M.B.,FCEyN
Journal of Chemical Physics | Year: 2011

The set of 1:1 and 2:1 complexes of XOOX′ (X, X′ H, CH 3) with lithium cation has been studied to determine if they are suitable candidates for chiral discrimination in an isotropic medium via nuclear magnetic resonance spectroscopy. Conventional nuclear magnetic resonance is unable to distinguish between enantiomers in the absence of a chiral solvent. The criterion for experimental detection is valuated by the isotropic part of nuclear shielding polarisability tensors, related to a pseudoscalar of opposite sign for two enantiomers. The study includes calculations at coupled Hartree-Fock and density functional theory schemes for 17O nucleus in each compound. Additional calculations for 1H are also included for some compounds. A huge static homogeneous electric field, perpendicular to the magnetic field of the spectromer, as big as ≈1.7 108 V m -1 should be applied to observe a shift of ≈1 ppm for 17O magnetic shielding in the proposed set of complexes. © 2011 American Institute of Physics.

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