RESUMO
The inhibition of cyclin-dependent kinase 4 (Cdk4) causes cell cycle arrest and restores a checkpoint that is absent in the majority of tumor cells. Compounds that inhibit Cdk4 selectively are targeted for treating cancer. Appropriate substitution of 2-aminoquinazolines is demonstrated to produce high levels of selectivity for Cdk4 versus closely related serine-threonine kinases.
Assuntos
Antineoplásicos/síntese química , Quinases Ciclina-Dependentes/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Quinazolinas/síntese química , Antineoplásicos/farmacologia , Quinase 4 Dependente de Ciclina , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Quinazolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
The chemical synthesis of a series of new penam sulfone derivatives bearing a 2beta-substituted-oxyimino and -hydrazone substituents, their beta-lactamase inhibitory properties against selected enzymes representing class A and C beta-lactamases are reported. The oxime containing penam sulfones strongly inhibited the Escherichia coli TEM-1 and Klebsiella pneumoniae cefotaximase (CTX-1) enzymes, but moderately inhibited the Pseudomonas aeruginosa 46012 cephalosporinase; while the 2beta-substituted-hydrazone derivatives were generally less active against these enzymes. Furthermore, most of the inhibitors enhanced the antibacterial activities of piperacillin (PIP) and ceftazidime (CAZ) particularly against TEM-1 and CTX-1 producing bacterial strains.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Sulfonas/síntese química , Sulfonas/farmacologia , Inibidores de beta-Lactamases , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Escherichia coli/enzimologia , Klebsiella pneumoniae/enzimologia , Testes de Sensibilidade Microbiana , Conformação Molecular , Pseudomonas aeruginosa/enzimologia , Relação Estrutura-Atividade , Sulfonas/química , beta-Lactamases/químicaRESUMO
A new class of inhibitors for cysteine proteases cathepsin B, L, K and S is described. These inhibitors are based on the beta-lactam ring designed to interact with the nucleophilic thiol of the cysteine in the active site of cysteine proteases. Some 3-acylamino-azetidin-2-one derivatives showed very potent inhibition activities for cathepsins L, K and S at the nanomolar or subnanomolar IC(50) values.
Assuntos
Azetidinas/síntese química , Inibidores de Cisteína Proteinase/síntese química , Azetidinas/farmacologia , Catepsina B/antagonistas & inibidores , Catepsina K , Catepsina L , Catepsinas/antagonistas & inibidores , Cisteína Endopeptidases , Inibidores de Cisteína Proteinase/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Lactamas/química , Elastase de Leucócito/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
A series of 6-substituted amino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one compounds was designed and synthesized as a new class of inhibitors for cysteine proteases cathepsins B, L, K, and S. One compound (5S,6S)-6-(N-benzyloxycarbonyl-L-phenylalanyl) amino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one showed excellent cathepsin L and K inhibition activity with IC(50) at a low nanomolar range.
Assuntos
Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Lactamas/química , Lactamas/farmacologia , Catepsinas/antagonistas & inibidores , Desenho de Fármacos , Concentração Inibidora 50 , Modelos Moleculares , Papaína/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis of a new series of 6-acylamino penam derivatives and their inhibition of cysteine proteases cathepsins B, L, K, and S is described. The 6-acylamino-penam sulfone compounds showed excellent cathepsin L, K, and S inhibition activity with IC(50) values in the nanomolar and subnanomolar range.