RESUMO
All eight stereoisomers of saxagliptin have been synthesized and evaluated for their inhibitory activity against DPP-IV. It was unambiguously confirmed that the configuration of saxagliptin was critical to potent inhibition of DPP-IV. Docking study was performed to elucidate the configuration-activity relationship of saxagliptin stereoisomers. Tyr662 and Tyr470 have been suggested as the key residues of DPP-IV interacting with the inhibitors. This work provides valuable information for further inhibitor design against DPP-IV.
Assuntos
Adamantano/análogos & derivados , Dipeptídeos/química , Dipeptidil Peptidase 4/metabolismo , Adamantano/síntese química , Adamantano/química , Adamantano/farmacologia , Sítios de Ligação , Domínio Catalítico , Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Ativação Enzimática/efeitos dos fármacos , Simulação de Acoplamento Molecular , Ligação Proteica , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Antidiabetic agents simultaneously inhibiting hepatic glucose production and stimulating hepatic glucose consumption could apply a better control over hyperglycemia. A series of oleanolic acid derivatives with bulky substituents at C-3 position were designed and synthesized in order to search for this kind of agents. All of the compounds were evaluated biologically in vitro using glycogen phosphorylase and HepG2 cells. The results indicated that several derivatives exhibited moderate-to-good inhibitory activities against glycogen phosphorylase. Compound 8g showed the best inhibition with an IC50 value of 5.4 µm. Moreover, most of the derivatives were found to increase the glucose consumption in HepG2 cells in a dose-dependent manner. The possible binding mode of compound 8g with glycogen phosphorylase was also explored by docking study. 8g was found to have hydrogen bonding interactions with Arg193, Arg310, and Arg60 of the allosteric site.
Assuntos
Hipoglicemiantes/síntese química , Ácido Oleanólico/análogos & derivados , Triazóis/síntese química , Sítios de Ligação , Ativação Enzimática/efeitos dos fármacos , Glucose/metabolismo , Glicogênio Fosforilase/antagonistas & inibidores , Glicogênio Fosforilase/metabolismo , Células Hep G2 , Humanos , Ligação de Hidrogênio , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Ácido Oleanólico/síntese química , Ácido Oleanólico/química , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacologia , Ligação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Triazóis/química , Triazóis/metabolismo , Triazóis/farmacologiaRESUMO
To study the target proteins of oleanolic acid, a series of novel photoaffinity probes were designed and synthesized. Their affinity for the target proteins was evaluated in an enzyme inhibition assay against glycogen phosphorylase, a known target protein of oleanolic acid. Among these compounds, probe 2 exhibited the most potent activity with an IC50 value of 5.98 µM, which was about 2.5-fold more potent than its parent compound oleanolic acid. The results showed that the synthesized photoaffinity probes retained the binding affinity for their target proteins, and might be used as powerful tools to fish out the target proteins of oleanolic acid.
Assuntos
Desenho de Fármacos , Ácido Oleanólico/síntese química , Ácido Oleanólico/metabolismo , Marcadores de Fotoafinidade/síntese química , Marcadores de Fotoafinidade/metabolismo , Técnicas de Química Sintética , Glicogênio Fosforilase/antagonistas & inibidores , Glicogênio Fosforilase/metabolismo , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Marcadores de Fotoafinidade/química , Marcadores de Fotoafinidade/farmacologia , Polietilenoglicóis/químicaRESUMO
Synthesis and biological evaluation of a novel series of substituted pentacyclic triterpene derivatives as potential PPARγ agoinsts and glycogen phosphorylase inhibitors have been described. Compounds 11 and 17 showed potent PPARγ agonistic activity and activated the transcription activity of PPARγ in a dose-dependent manner. On the other hand, eleven compounds exhibited moderate inhibitory activity against rabbit muscle glycogen phosphorylase a (RMGPa), and triterpene 10 was the best one. Structure-activity relationship (SAR) is also discussed.
Assuntos
Glicogênio Fosforilase Muscular/antagonistas & inibidores , PPAR gama/agonistas , Triterpenos Pentacíclicos/síntese química , Triterpenos Pentacíclicos/farmacologia , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Molecular , Triterpenos Pentacíclicos/química , Ligação Proteica/efeitos dos fármacos , Coelhos , Rosiglitazona , Relação Estrutura-Atividade , Tiazolidinedionas/química , Tiazolidinedionas/farmacologiaRESUMO
To explore the molecular mechanisms of oleanolic acid, two novel photoaffinity probes were synthesized based on the structure-activity relationship reported previously. Their potency were evaluated in an enzyme inhibition assay against rabbit muscle glycogen phosphorylase a (RMGPa), a known target protein of oleanolic acid. The inhibitory activity of probe 2 was only about two-fold less potent than the mother compound oleanolic acid. The photoaffinity labeling experiments were also performed and two proteins were specifically tagged by probe 2. The results suggest that the synthesized probes could be used as powerful tools to isolate and identify the target proteins of oleanolic acid.
