RESUMEN
Potential prodrugs of inhibitors of VEGF-induced angiogenesis have been investigated. The prodrug systems studied were the 4-nitrobenzyl, 2-nitrophenylacetyl and 3-methyl-3-(3,6-dimethylbenzo-1,4-quinon-2-yl)butanoyl groups, readily attached to acidic OH or NH groups in drug molecules, and released upon bioreductive activation. The anti-angiogenic compounds studied were the pyrrolylmethylidenyl oxindole SU5416 (semaxanib) and its novel 6-hydroxy derivative. The potentially pro-anti-angiogenic compounds were assayed for their ability to block VEGF-induced angiogenesis in HUVECS in comparison to the free agents.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/farmacología , Indoles/síntesis química , Indoles/farmacología , Profármacos/síntesis química , Profármacos/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Células Cultivadas , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Relación Estructura-Actividad , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
[reaction: see text] A series of structurally simplified luminacin analogues devoid of the epoxide ring are assembled in a stereocontrolled manner from 2,4-dimethoxybenzaldehyde using a syn-selective aldol reaction as the key step. The success of the approach is critically dependent on the nature and extent of the alcohol protecting groups. The synthetic analogues inhibit VEGF-stimulated angiogenesis in an in vitro assay indicating that the epoxide is not essential for biological activity in this compound class.