Sun, Guoxuan; (2021) Synthesis of Novobiocin Based Anti-cancerous Hsp90 C- terminal Inhibitors. Doctoral thesis (Ph.D), UCL (University College London).

Preview

Text Sun-G__thesis.pdf Download (15MB) | Preview

Abstract

The research described in this thesis focuses on heat shock protein 90 kDa (Hsp90), which is a molecular chaperone that contributes to the correct folding of around 200 proteins. It is an important protein that is associated with cancer survival and has been a focus of anticancer drug development for over two decades. Previous studies have shown that novobiocin (an FDA approved drug) acts as a weak inhibitor of Hsp90 via binding to the C-terminal domain (CTD) of Hsp90 and that modification of novobiocin has been shown to increase its anticancer activity. In this thesis, we designed and synthesized a series of analogues based on 4’ substituted novobiocin that focused on four modifications to improve its anticancer efficacy: In chapter 2 we aimed to: 1) replace the sugar moieties attached on the 4'-hydroxyl group; 2) substitute the 3'-amino group; 3) replace the novoise group with other sugars; in chapter 3 we aim to: 4) Develop of a covalent targeting strategy to identify any active cysteine residues of Hsp90 CTD, which could react with Michael acceptors added to novobiocin 4’. We designed and synthesized a number of glycosidic type novobiocin analogues via an optimized phase transfer catalysis. The resulted compounds showed increased antiproliferative activity. Protected sugar moieties are far less active than deprotected ones, however, difficulties of deprotection limited further development of such types of inhibitors. Nevertheless, we report compound 68, an indole-amide analogue of novobiocin, to be a new lead structure with IC50 = 23.4 μM. Also, 4’-Acrylate Michael acceptor type novobiocin Hsp90 inhibitors mildly improve anti-proliferative activity and 4’ substitution of cinnamic or sulfone fluoride group significantly increase the drug potency. Proteomic analysis of drug-Hsp90 complex confirmed the covalent modification of C597/C598. Overall, our project added new synthetic and biological knowledge into the design of non-covalent Hsp90 CTD inhibitors, more importantly, opened the gate for covalent Hsp90 CTD inhibitors drug design for the first time. Non-covalent candidate 68 and Michael acceptor type covalent candidate 108, 138 are identified as lead structures.

Download activity - last month

Export as JSONXMLCSV

Download activity - last 12 months

Export as CSVXMLJSON

Downloads by country - last 12 months

Export as XMLJSONCSV

Archive Staff Only

View Item