Studies on the inhibitors for enzymes containing $Zn^{2+}$ at the active site and total synthesis of gelastatins

Abstract

For past a few years, we had focused on the studies for two enzymes among enzymes containing $Zn^{2+}$, FTase and TACE. FTase catalyzes the transfer of farnesyl unit from FPP to the thiol group in cysteine residue of C-terminus in Ras protein. It was believed that inhibiting the farnesylation of Ras protein would be the therapeutic target for various forms of cancer. With this point of view, we have carried out the studies on FTase inhibitor through syntheses of various compounds, then the evaluation of their biological activity. At this time, computer modeling played a crucial role in elucidating SAR (structure activity relationship) of inhibitors. With these efforts for the studies on the FTase inhibitors, we finally opened the untapped novel way to develop a potent FTase inhibitor. Rheumatoid Arthritis (RA) is a chronic inflammatory autoimmune disease affecting 0.5-1 % of population worldwide. One of attracting targets for RA is tumor necrosis factor alpha (TNF-α), an important cytokine in RA pathological progress $^{49}$. TNF-α converting enzyme (TACE) catalyzes the manifestation of mature TNF-α and so it is being supposed that TACE inhibitors would be a successful therapy for RA. Gelastatins, isolated from the culture broth of Westerdykella multispora, showed potent inhibitory activity against TACE. However, they showed activities for other metalloproteinases as well as TACE. To overcome the absence of selectivity, we designed and synthesized various TACE’s analogues and evaluated their biological activities and also found a good scaffold for TACE inhibitor through the modification of pyrone, core structure in Gelastatin.