RESUMO
Continuous efforts in microwave-assisted synthesis and the structure-activity relationships' (SARs) studies of novel modified 9-oxo-thiazolo[5,4-f]quinazoline-2-carbonitriles, allowed identification of new amidine and imidate derivatives as potent and dual CDK1/GSK-3 inhibitors. Combination of lead optimization and molecular modeling studies allowed identification of a dual CDK1/GSK-3 inhibitor (compound 13d) with submicromolar values.
Assuntos
Proteína Quinase CDC2/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Modelos Moleculares , Nitrilas/síntese química , Nitrilas/farmacologia , Quinazolinas/síntese química , Quinazolinas/farmacologia , Espectroscopia de Ressonância Magnética , Espectrofotometria InfravermelhoRESUMO
In an effort to identify new protein kinase inhibitors with increased potency and selectivity, we have developed the microwave-assisted synthesis of thiazolo[5,4-f]quinazolin-9-ones. The effects of eighteen derivatives on CDK1/cyclin B, CDK5/p25, and GSK-3 were investigated. Several turned out to inhibit GSK-3 in the micromolar range. Molecular modeling studies suggest that the most selective GSK-3 inhibitors 7a-d bind into the ATP-binding site through a key hydrogen bond interaction with Val135 and target the specific hydrophobic backpocket of the enzyme.
Assuntos
Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinazolinas/farmacologia , Tiazóis/farmacologia , Trifosfato de Adenosina/química , Sítios de Ligação , Cristalografia por Raios X , Quinases Ciclina-Dependentes/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/efeitos da radiação , Ligação de Hidrogênio , Micro-Ondas , Modelos Moleculares , Quinazolinas/química , Quinazolinas/efeitos da radiação , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/efeitos da radiaçãoRESUMO
The microwave-assisted synthesis of a family of 2,8-substituted thiazoloquinazolinones is described. The preliminary evaluation of the antiproliferative activity and the capacity of these molecules to inhibit CDKs and GSK-3 are reported. A lead compound was identified, constituting a scaffold from which more potent inhibitors could be designed.
Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinazolinas/síntese química , Quinazolinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/efeitos da radiação , Humanos , Micro-Ondas , Estrutura Molecular , Quinazolinas/efeitos da radiação , Relação Estrutura-AtividadeRESUMO
The interest of microwaves in drug discovery and multi-step synthesis is exposed with the aim of describing our strategy. These studies are connected with our work on the synthesis of original heterocyclic compounds with potential pharmaceutical value. Reactions in the presence of solvent and solvent-free synthesis can be realised under a variety of conditions; for some of these selected results are given, and where available, results from comparison with the same solvent-free conditions but with classical heating are given.
Assuntos
Química Orgânica/métodos , Desenho de Fármacos , Micro-Ondas , Carbono/química , Calefação , Modelos Químicos , Nitrilas/química , Solventes/química , TemperaturaRESUMO
Novel 6-substituted thiazolocarbazole derivatives have been synthesized under microwave irradiation via the corresponding imino-1,2,3-dithiazoles. In vitro antitumor potential of these polyheterocyclic compounds was evaluated. Among all the tested thiazolocarbazoles, compound 10 is the most effective in inhibiting cell growth.