RESUMEN
Cathepsin K (CatK) is a cysteine protease known for its potent collagenolytic activity, being recognized as an important target to the development of therapies for the treatment of bone disorders. Epoxypeptidomimetics have been reported as potent inhibitors of cathepsins, thus in this work we present a green synthesis of new peptidomimetics by using a one-pot asymmetric epoxidation/Ugi multicomponent reaction. The compounds were evaluated against CatK showing selectivity when compared with cathepsin L, with an inhibition profile in the low micromolar IC50 range. Investigation of the mechanism of action carried out for compounds LSPN428 and LSPN694 suggested a mixed inhibition mode and docking studies allowed a better understanding about interactions of inhibitors with the enzyme.
Asunto(s)
Catepsina K/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/química , Compuestos Epoxi/química , Peptidomiméticos/química , Dominio Catalítico , Catepsina K/química , Catepsina K/metabolismo , Inhibidores de Cisteína Proteinasa/síntesis química , Inhibidores de Cisteína Proteinasa/metabolismo , Compuestos Epoxi/síntesis química , Compuestos Epoxi/metabolismo , Tecnología Química Verde , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Peptidomiméticos/síntesis química , Peptidomiméticos/metabolismo , Unión Proteica , Relación Estructura-ActividadRESUMEN
Cathepsin L plays important roles in physiological processes as well as in the development of many pathologies. Recently the attentions were turned to its association with tumor progress what makes essential the development of more potent and selective inhibitors. In this work, epoxipeptidomimetics were investigated as new cathepsin inhibitors. This class of compounds is straightforward obtained by using a green one-pot asymmetric epoxidation/Passerini 3-MCR. A small library of 17 compounds was evaluated against cathepsin L, and among them LSPN423 showed to be the most potent. Investigations of the mechanism suggested a tight binding uncompetitive inhibition.
Asunto(s)
Amidas/química , Catepsina L/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Amidas/metabolismo , Amidas/farmacología , Animales , Antiparasitarios/química , Antiparasitarios/metabolismo , Antiparasitarios/farmacología , Catepsina L/metabolismo , Inhibidores de Cisteína Proteinasa/metabolismo , Inhibidores de Cisteína Proteinasa/farmacología , Concentración 50 Inhibidora , Parásitos/efectos de los fármacos , Parásitos/enzimología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel potent xanthine oxidase inhibitor, 3-nitrobenzoyl 9-deazaguanine (LSPN451), was selected from a series of 10 synthetic derivatives. The enzymatic assays were carried out using an on-flow bidimensional liquid chromatography (2D LC) system, which allowed the screening¸ the measurement of the kinetic inhibition constant and the characterization of the inhibition mode. This compound showed a non-competitive inhibition mechanism with more affinity for the enzyme-substrate complex than for the free enzyme, and inhibition constant of 55.1±9.80 nM, about thirty times more potent than allopurinol. Further details of synthesis and enzymatic studies are presented herein.
