RESUMO
Herein a series of Geniposide derivatives were designed, synthesized and evaluated as protein tyrosine phosphatase 1B (PTPlB) inhibitors. Most of these compounds exhibited potent in vitro PTP1B inhibitory activities, the representative 7a and 17f were found to be the most potent inhibitors against the enzyme with IC50 values of 0.35 and 0.41 µM, respectively. More importantly, they showcased 4 to10-fold selectivity over SHP2 and 3-fold over TCPTP. Further biological activity studies revealed that compounds 7a, 17b and 17f could effectively enhance insulin-stimulated glucose uptake with no significant cytotoxicity. Subsequent molecular docking and structural activity relationship analyses demonstrated that the glucose scaffold, benzylated glycosyl groups, and arylethenesulfonic acid ester significantly impact on the activity and selectivity.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Iridoides/síntese química , Iridoides/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Técnicas de Química Sintética , Inibidores Enzimáticos/química , Glucose/metabolismo , Concentração Inibidora 50 , Insulina/farmacologia , Iridoides/química , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Ácidos Sulfônicos/químicaRESUMO
Protein tyrosine phosphatase 1B (PTP1B) has been considered as a promising therapeutic target for type 2 diabetes mellitus (T2DM) and obesity due to its key regulating effects in insulin signaling and leptin receptor pathways. In this work, a series of cis- and trans-pyrrolidine bisarylethenesulfonic acid esters were prepared and their PTP1B inhibitory potency, selectivity and membrane permeability were evaluated. These novel stereoisomeric molecules especially trans-isomers exhibited remarkable inhibitory activity, significant selectivity as well as good membrane permeability (e.g. compound 28a, IC50â¯=â¯120, 1940 and 2670â¯nM against PTP1B, TCPTP and SHP2 respectively, and Pappâ¯=â¯1.74â¯×â¯10-6â¯cm/s). Molecular simulations indicated that trans-pyrrolidine bisarylethenesulfonic acid esters yielded the stronger binding affinity than their cis-isomers by constructing more interactions with non-catalytic sites of PTP1B. Further biological activity studies revealed that compound 28a could enhance insulin-stimulated glucose uptake and insulin-mediated insulin receptor ß (IRß) phosphorylation with no significant cytotoxicity.