Assuntos
Antibacterianos/farmacologia , Depsipeptídeos/farmacologia , Lysobacter/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Depsipeptídeos/síntese química , Depsipeptídeos/química , Desenho de Fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
Tyropeptin A, a potent proteasome inhibitor, was isolated from the culture broth of Kitasatospora sp. MK993-dF2. We synthesized the derivatives of tyropeptin A to enhance its inhibitory potency. Among the synthesized derivatives, the most potent compound, TP-104, exhibited a 20-fold inhibitory potency enhancement for chymotrypsin-like activity of 20S proteasome compared to tyropeptin A. Additionally, TP-110 specifically inhibited the chymotrypsin-like activity, but did not inhibit the post-glutamyl-peptide hydrolyzing (PGPH) and the trypsin-like activities of 20S proteasome. In vitro TP-110 strongly inhibited the growth of various cell lines.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Dipeptídeos/química , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Inibidores de Proteassoma , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimotripsina/antagonistas & inibidores , Quimotripsina/química , Dipeptídeos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Complexo de Endopeptidases do Proteassoma/químicaRESUMO
Tyropeptin A, a new potent proteasome inhibitor, was produced by Kitasatospora sp. MK993-dF2. To enhance the inhibitory potency of tyropeptin A, we constructed the structural model of tyropeptin A bound to the site responsible for the chymotrypsin-like activity of mammalian 20S proteasome. Based on these modeling experiments, we designed and synthesized several derivatives of tyropeptin A. Among them, the most potent compound, TP-104, exhibited a 20-fold enhancement in its inhibitory potency compared to tyropeptin A. Additionally, TP-110 specifically inhibited the chymotrypsin-like activity, but did not inhibit the PGPH and the trypsin-like activities.
Assuntos
Dipeptídeos/síntese química , Inibidores Enzimáticos/síntese química , Complexos Multienzimáticos/antagonistas & inibidores , Inibidores de Proteassoma , Sítios de Ligação , Quimotripsina/antagonistas & inibidores , Dipeptídeos/farmacologia , Desenho de Fármacos , Endopeptidases/metabolismo , Inibidores Enzimáticos/farmacologia , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
Planar structures of tripropeptins (TPPs) were elucidated by spectroscopic studies including various NMR measurements. Stereochemistry of constituent amino acids of tripropeptin C (TPPC) (3) was identified by marfey's method except hydroxyproline which was determined by studies of NMR and CD spectra. The absolute structure of 3 was determined by analyses of the fragments obtained by Birch reduction and LiBH4 reduction of 3. The configuration of the fatty acid, isolated from acid hydrolysate of 3, was determined to be (3R)-hydroxy-13-methyltetradecanoic acid from MS, NMR spectra and negative sign of the optical rotation.
