Issue 8, 2023

Furan-based inhibitors of pyruvate dehydrogenase: SAR study, biochemical evaluation and computational analysis

Abstract

Suppression of pyruvate dehydrogenase complex (PDHc) is a mechanism for cancer cells to manifest the Warburg effect. However, recent evidence suggests that whether PDHc activity is suppressed or activated depends on the type of cancer. The PDHc E1 subunit (PDH E1) is a thiamine pyrophosphate (TPP)-dependent enzyme, catalysing the first and rate-limiting step of PDHc; thus, there is a need for selective PDH E1 inhibitors. There is, however, inadequate understanding of the structure–activity relationship (SAR) and a lack of inhibitors specific for mammalian PDH E1. Our group have reported TPP analogues as TPP-competitive inhibitors to study the family of TPP-dependent enzymes. Most of these TPP analogues cannot be used to study PDHc in cells because (a) they inhibit all members of the family and (b) they are membrane-impermeable. Here we report derivatives of thiamine/TPP analogues that identify elements distinctive to PDH E1 for selectivity. Based on our SAR findings, we developed a series of furan-based thiamine analogues as potent, selective and membrane-permeable inhibitors of mammalian PDH E1. We envision that our SAR findings and inhibitors will aid work on using chemical inhibition to understand the oncogenic role of PDHc.

Graphical abstract: Furan-based inhibitors of pyruvate dehydrogenase: SAR study, biochemical evaluation and computational analysis

Supplementary files

Article information

Article type
Paper
Submitted
16 Dec 2022
Accepted
26 Jan 2023
First published
27 Jan 2023
This article is Open Access
Creative Commons BY license

Org. Biomol. Chem., 2023,21, 1755-1763

Furan-based inhibitors of pyruvate dehydrogenase: SAR study, biochemical evaluation and computational analysis

A. H. Y. Chan, T. C. S. Ho, D. R. Parle and F. J. Leeper, Org. Biomol. Chem., 2023, 21, 1755 DOI: 10.1039/D2OB02272A

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