Uso de inhibidores de histona deacetilasas como compuestos angiogénicos en el tratamiento de úlceras de pie diabético

Abstract

Las úlceras de píe diabético y la poca vascularización en extremidades inferiores, aumentan el riesgo de amputaciones en pacientes con diabetes mellitus tipo 2. Por esto, buscamos inductores de la angiogénesis usando la señalización de los inhibidores de histona deacetilasa (iHDAC) capaces de activar al factor inducible por hipoxia-alfa (HIF-1α), principal activador de angiogénesis. Se reposicionaron compuestos aprobados por la FDA para disminuir posibles efectos citotóxicos, obteniendo 3 moléculas con el mismo grupo funcional que el inhibidor previamente reportado por Ottosson. Se desarrolló un modelo ex vivo de anillos aórticos de ratón para medir la angiogénesis obteniendo resultados positivos en 2 moléculas. La 2-aminoacetanilida y N-boc-1,2-fenilendiamina incrementaron la proliferación en los anillos aórticos siendo candidatos al reposicionamiento como iHDAC.

The diabetic foot ulcer and the lack of vascularization in low extremities, increase the risk of amputation in patients with diabetes mellitus type 2. The present study focused on the search of angiogenesis inducers, based on the pathway of the histone deacetylase inhibitors (HDACi). These compounds are capable to activate the hypoxia inducible factor (HIF-1α,) the main angiogenesis activator and this activity is reduced in the diabetic foot. Based on these inhibitors, it was performed a drug repositioning on FDA approved molecules to reduce the cytotoxic effects of the HDACi. The docking analysis suggested 3 candidate molecules with the same functional group of the inhibitors previously reported by Ottosson and collaborators. We developed an ex-vivo model of mouse aortic rings to measure the angiogenesis obtaining positive results in 2 of the 3 tested molecules, the 2-aminoacetanilide and the N-boc-1,2-phenylendiamne are capable to increase the proliferation in the aortic rings, the third molecule 1,3-diphenylurea doesn’t showed the same effect maybe because their physicochemical properties prevented the interaction with the matrix. Our results suggest that although the candidate molecules have not a reported activity against the histone deacetylase, they can be repositioning like an HDACi promoting angiogenesis.