RESUMEN
The Ugi reaction has been successfully applied to the synthesis of novel arginase inhibitors. In an effort to decrease conformational flexibility of the previously reported series of 2-amino-6-boronohexanoic acid (ABH) analogs 1, we designed and synthesized a series of compounds, 2, in which a piperidine ring is linked directly to a quaternary amino acid center. Further improvement of in vitro activity was achieved by adding two carbon bridge in the piperidine ring, that is, tropane analogs 11. These improvements in activity are rationalized by X-ray crystallography analysis, which show that the tropane ring nitrogen atom moves into direct contact with Asp202 (arginase II numbering). The synthetic routes described here enabled the design of novel arginase inhibitors with improved potency and markedly different physico-chemical properties compared to ABH. Compound 11c represents the most in vitro active arginase inhibitor reported to date.
Asunto(s)
Aminoácidos/química , Aminoácidos/farmacología , Aminocaproatos/química , Aminocaproatos/farmacología , Arginasa/antagonistas & inhibidores , Compuestos de Boro/química , Compuestos de Boro/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Aminoácidos/síntesis química , Aminocaproatos/síntesis química , Arginasa/metabolismo , Compuestos de Boro/síntesis química , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Humanos , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
Substitution at the alpha center of the known human arginase inhibitor 2-amino-6-boronohexanoic acid (ABH) is acceptable in the active site pockets of both human arginase I and arginase II. In particular, substituents with a tertiary amine linked via a two carbon chain show improved inhibitory potency for both enzyme isoforms. This potency improvement can be rationalized by X-ray crystallography, which shows a water-mediated contact between the basic nitrogen and the carboxylic acid side chain of Asp200, which is situated at the mouth of the active site pocket of arginase II (Asp181 in arginase I). We believe that this is the first literature report of compounds with improved arginase inhibitory activity, relative to ABH, and represents a promising starting point for further optimization of in vitro potency and the identification of better tool molecules for in vivo investigations of the potential pathophysiological roles of arginases.
