| Description |
Hepatitis C virus (HCV) infection has become a leading killer worldwide, affecting more than 170 million people and leading to cirrhosis of the liver, end-stage liver disease, and hepatocellular carcinoma. Current therapies for HCV are associated with significant side effects, as well as increased resistance. Therefore, there is a clear need for a less toxic and more effective therapy. RNA is becoming an important therapeutic target, despite the challenge associated with developing molecules targeting RNA. The HCV internal ribosome entry site (IRES) located at the 5 untranslated region of the viral RNA has become a most attractive therapeutic target. Domain II of the HCV IRES has a 90o bent helical structure, which is crucial for the function of the IRES. Benzimidazole based HCV replication inhibitors that exert their activity by altering the structure of the domain IIa of the HCV IRES have been reported. The Rainier group, in collaboration with the Davis, Cheatham and Hagedorn groups of the University of Utah, plan to reach the goal of developing efficient HCV therapeutics. The plan centers around utilizing the previously reported synthesis of quaternary substituted indolines and thiopyranylindolines by Rh(II) mediated diazo decomposition to examine the scope of potential HCV inhibitors. A serotonin derivative was coupled with a vinyl diazo ester in the presence of Rh2(OAc)4 to provide a quaternary substituted indoline, which after cyclization with TFA provided the pyrroloindoline based potential HCV inhibitors. Chaetomin was isolated from Chaetomium sp. and was found to possess antibiotic effects, immunomodulatory activity, and anti cancer activity. Thus, the fascinating architecture, as well as its striking biological activity, have made chaetomin an attractive synthetic target. The indole-diketopiperazine bridge in chaetomin is an important structural feature of its northern hemisphere. The bridgehead carbanion in the epidithiodiketopiperazine moiety was quenched with a skatole derivative to produce an indole-diketopiperazine coupled product. Outlined here are the studies directed toward the synthesis of pyrroloindoline based potential HCV inhibitors, and the synthesis of the indole-diketopiperazine bridge in chaetomin. |
