Design and Synthesis of Thiamine Pyrophosphate (TPP) Analogues for Investigating the Structure-Activity Relationship (SAR) of Inhibitors of TPP-dependent Enzymes

Abstract

Thiamine pyrophosphate (TPP), the bioactive form of vitamin B1, is an essential coenzyme needed for processes of cellular metabolism in all organisms. TPP-dependent enzymes all require the coenzyme TPP for catalytic activity, although individual members vary significantly in substrate preferences and biochemical reactions. To study these enzymes by chemical inhibition, the most popular way is to use thiamine/TPP analogues, which typically feature a neutral aromatic ring in place of TPP’s positive thiazolium ring. In response to the growing demand in understanding the roles of TPP-dependent enzymes and their pathways within biological systems, development of membrane-permeable thiamine analogues is pursued. In this PhD project, novel analogues of thiamine-based compounds have been designed, synthesised and evaluated on a variety of TPP-dependent enzymes. With the established structure-and-activity relationship of our analogues in hand, we developed membrane-permeable tools: some are selective to a given member while some possess broad inhibitory activities against the enzyme family.