Novel Antihypertensive Prodrug from Grape Seed Proanthocyanidin Extract via Acid-Mediated Depolymerization in the Presence of Captopril: Synthesis, Process Optimization, and Metabolism in Rats

Grape seed extract contains a high content of proanthocyanidins that can be depolymerized into C-4-substituted (epi)­catechin derivatives in the presence of nucleophiles. However, the biological and medicinal values of depolymerization products have been rarely investigated. Recently, we developed a novel depolymerization product (−)-epicatechin-4β-<i>S</i>-captopril methyl ester (ECC) derived from the reaction of grape seed proanthocyanidin extract with captopril in the presence of acidified methanol. A central composite design was employed to select the most appropriate depolymerization temperature and time to obtain the target product ECC with a high yield. A total of 16 metabolites of ECC in rat urine, feces, and plasma were identified using liquid chromatography quadrupole time-of-flight tandem mass spectrometry. The <i>in vivo</i> results suggested that ECC could release captopril methyl ester and epicatechin, followed by the generation of further metabolites captopril and epicatechin sulfate conjugates. Therefore, ECC may be used as a potential prodrug with synergistic or additive hypotensive effects