- Guanidinium-based derivatives: Searching for new kinase inhibitors
-
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.
- Diez-Cecilia, Elena,Kelly, Brendan,Perez, Concepcion,Zisterer, Daniela M.,Nevin, Daniel K.,Lloyd, David G.,Rozas, Isabel
-
-
Read Online
- α2-adrenoceptor antagonists: Synthesis, pharmacological evaluation, and molecular modeling investigation of pyridinoguanidine, pyridino-2-aminoimidazoline and their derivatives
-
We have previously identified phenylguanidine and phenyl-2-aminoimidazoline compounds as high affinity ligands with conflicting functional activity at the α2-adrenoceptor, a G-protein-coupled receptor with relevance in several neuropsychiatric conditions. In this paper we describe the design, synthesis, and pharmacological evaluation of a new series of pyridine derivatives [para substituted 2- and 3-guanidino and 2- and 3-(2-aminoimidazolino)pyridines, disubstituted 2-guanidinopyridines and N-substituted-2-amino-1,4-dihydroquinazolines] that were found to be antagonists/inverse agonists of the α2-adrenoceptor. Furthermore, the compounds exert their effects at the α2-adrenoceptor both in vitro in human prefrontal cortex tissue and in vivo in rat brain as shown by microdialysis experiments. We also provide a docking study at the α2A- and α2C-adrenoceptor subtypes demonstrating the structural features required for high affinity binding to the receptor.
- Kelly, Brendan,McMullan, Michela,Muguruza, Carolina,Ortega, Jorge E.,Meana, J. Javier,Callado, Luis F.,Rozas, Isabel
-
supporting information
p. 963 - 977
(2015/01/30)
-
- Guanidine-based α2-adrenoceptor ligands: Towards selective antagonist activity
-
Depression has been linked to a selective increase in the high affinity conformation of the α2-adrenergic autoreceptors (α2-ARs) in the human brain as well as to an overexpression of α2-ARs in the hippocampus and cerebral cortex. Thus, the development of novel α2-AR antagonists represents an attractive source of new antidepressants. This paper describes the design, synthesis and pharmacological evaluation of 30 new guanidinium and 2-iminoimidazolidinium as potential α2-AR antagonists. In order to design this new series of α2-AR antagonists, a pharmacophore model was developed using the GALAHAD software. This study suggested that increased substitution in the space surrounding the cationic guanidine moiety might lead selectively to antagonist activity. Following the preparation of compounds incorporating this feature and competitive radioligand binding, [ 35S]GTPγS functional assays revealed that this structural modification affords exclusively α2-AR antagonists, in contrast with the analogous unsubstituted compounds in which a mixture of antagonist/agonist activities was previously observed.
- O'Donovan, Daniel H.,Muguruza, Carolina,Callado, Luis F.,Rozas, Isabel
-
supporting information
p. 242 - 254
(2014/06/24)
-
- New methods for the preparation of aryl 2-iminoimidazolidines
-
A divergent strategy for the synthesis of 1-aryl- and 2-aryl-2- iminoimidazolidines is presented. Cyclization of N-Boc-N′-aryl-N″- (2-hydroxyethyl)guanidines in the presence of methanesulfonyl chloride and triethylamine or sodium hydride at 0 °C affords the corresponding 2-iminoimidazolidines in good yields.
- O'Donovan, Daniel H.,Rozas, Isabel
-
p. 4532 - 4535
(2012/10/07)
-
- A concise synthesis of asymmetrical N,N′-disubstituted guanidines
-
We present a new and concise method for the preparation of asymmetrical N,N′-disubstituted guanidines starting from thiourea via the reaction of N-Boc-protected N′-alkyl/aryl substituted thioureas with an amine in the presence of mercury(II) chloride and
- O'Donovan, Daniel H.,Rozas, Isabel
-
supporting information; experimental part
p. 4117 - 4119
(2011/09/19)
-
- N, N-di-boc-substituted thiourea as a novel and mild thioacylating agent applicable for the synthesis of thiocarbonyl compounds
-
Stable and readily available N,N-di-Boc-substituted thiourea, when activated with trifluoroacetic acid anhydride, was used as a novel thioacylating agent. Through the thioacylation of nucleophiles, such as amines, alcohols, thiols, sodium benzene-thiolate
- Yin, Biao-Lin,Liu, Zhao-Gui,Zhang, Jian-Cun,Li, Zheng-Rong
-
experimental part
p. 991 - 999
(2010/06/11)
-
- An efficient method for the synthesis of disubstituted thioureas via the reaction of N,N′-di-Boc-substituted thiourea with alkyl and aryl amines under mild conditions
-
An efficient method for the synthesis of disubstituted thioureas via the reaction of N,N′-di-Boc-substituted thiourea 5 with alkyl and aryl amines under mild conditions has been developed. In the presence of NaH as a base, trifluoroacetic anhydride (TFAA)
- Yin, Biaolin,Liu, Zhaogui,Yi, Mingjun,Zhang, Jiancun
-
p. 3687 - 3690
(2008/09/20)
-