Studies on the synthesis and pharmacophore on metalloproteinase inhibitors ; synthesis of gelastatin and gelastatin analogs

Abstract

The first practical synthesis of Gelastatins, a natural product isolated from the culture broth of westerdykella multispora F 50733 found in soil sample in 1997, and Gelastatin-derived analogs have been studied. Gelastatins were found to exhibit impressive biological activities, including inhibition of Gelatinase A (MMP-2) and inhibition of tumor necrosis factor-$\alpha$ converting enzyme (TACE). Gelastins contain a characteristic dihydropyrane framework and a conjugated triene systems which consist of cis and trans configurations. Several approaches for the lactone ring system was attempted and total synthesis of Gelastatins was completed from Meldrum’s acid. Also, the design, synthesis and structure-activity relationship of a series of Gelastatin-derived analogs as inhibitors of the MMP-2 and TACE was studied. From the MMP-2 and TACE inhibition studies, it was concluded that lactone ring system and hydrophobic group of site III are essential for the substrate recognition by the enzyme. Based on the activities of Gelastatins and Gelastin-derived analogs, we suggested a new pharmacophore model. During the course of our studies on the synthesis of Gelastatins containing a key framework, dihydropyran ring, a new synthetic method constructing the valuable template and combinatorial libraries via ring closing metathesis, cross metathesis, and cycloaddition reaction was developed.