Synthetic and computational efforts toward the understanding and development of novobiocin-derived inhibitors of Hsp90

Abstract

As C−terminal inhibitors of a 90−kDa heat shock protein (Hsp90), novobiocin and its derivatives are a significant part of an emerging class of cancer chemotherapeutic agents. Previous studies have shown that analogues of the coumarin and benzamide moieties of novobiocin exhibit more than a 1000−fold improvement in activity over the parent compound. This thesis describes synthetic efforts toward the completion of noviose mimics to determine moieties that are critical for binding or can be altered for improved activity. Additionally, in the absence of a co−crystal structure for the Hsp90 C−terminus, there is a need to develop an accurate model to assist in efficient drug design. This work describes the use of molecular modeling and docking software to design new, potentially useful models of C−terminal interactions.