Synthesis of Novel Thiol-Containing Citric Acid Analogues. Kinetic Evaluation of These and Other Potential Active-Site-Directed and Mechanism-Based Inhibitors of ATP Citrate Lyase

Roland E. Dolle, Andy Gribble, Tracey Wilkes, Lawrence I. Kruse, Drake Eggleston, Barbara A. Saxty, Timothy N.C. Wells, Pieter H.E. Groot

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

ATP citrate lyase is an enzyme involved in mammalian lipogenesis and cholesterogenesis. Inhibitors of the enzyme represent a potentially novel class of hypolipidemic agents. Citric acid analogues 5–16 bearing electrophilic and latent electrophilic substituents were synthesized and evaluated as irreversible inhibitors of the enzyme. The design of these agents was based on the classical enzymatic mechanism where an active-site nucleophile (thiol) was believed to be critically involved in catalysis. Reversible inhibition CKi’s ranging from ca. 20 to 500 μM) was observed for compounds 5, 10, and 12–16. Compounds 6–9 and 11 had no appreciable affinity for enzyme (Ki < in 1 mM). Time-dependent inactivation of the enzyme by 5–16 was not detected following long incubation times (<1 h, 37 °C) at 2 mM inhibitor concentrations.

Original languageEnglish
Pages (from-to)537-543
Number of pages7
JournalJournal of Medicinal Chemistry
Volume38
Issue number3
DOIs
StatePublished - Feb 1 1995
Externally publishedYes

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