Syntheses, Structures, and Enzymatic Evaluations of Hemiacylcarnitiniums, a New Class of Carnitine Acyltransferase Inhibitors

Richard D. Gandour, Noelle L. Blackwell*, William J. Colucci, Chang Chung, Loran L. Bieber, Rona R. Ramsay, Eric P. Brass, Frank R. Fronczek

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

The syntheses of (2S,6R)-6-(carboxymethyl)-2-hydroxy-2,4,4-trimethylmorpholinium chloride (hemiacetylcamitinium, HAC), (2S,6R)-6-(carboxymethyl)-2-ethyl-2-hydroxy-4,4-dimethylmorpholinium bromide (hemipropanoylcarnitinium, HPrC), and (2S,6R)-6-(carboxymethyl)-2-hydroxy-4,4-dimethyl-2-phenylmorpholinium chloride monohydrate (hemibenzoylcarnitinium, HBC) are described. The crystal structure of HAC is reported and compared with crystal structures of HPrC, HBC, carnitine·HCl, acetylcarnitine·HCl, and acetylcamitine·HCl·H2O. HAC, HPrC, and HBC inhibit carnitine acetyltransferase (CAT) activity from multiple biological sources. The best inhibitor, HAC, has Ki of 69 ± 5 μM with rat liver peroxisomal CAT. HAC binds more strongly than the natural substrate (and isomer), acetylcarnitine. HAC also strongly inhibits, Ki = 92 ± 14 μM, CAT from rat heart mitochondria. HPrC inhibits pigeon breast CAT with a Ki, of 200 ± 30 μM. HBC inhibits pigeon breast CAT, rat heart mitochondrial CAT, rat liver mitochondrial CAT, and rat liver peroxisomal carnitine octanoyltransferase (COT), with values of Ki of 3500 ± 500,2400 ± 70,1670 ± 70, and 1100 ± 100 μM, respectively. Racemic 6-(carboxymethyl)-2-hydroxy-2-pentadecyl-4,4-dimethylmorpholinium bromide (hemipalmitoylcamitinium, HPC) strongly inhibits (Ki = 2 ± 0.3 μM) beef liver mitochondrial CPTi. In summary, hemiacylcarnitiniums show promise as a general class of carnitine acyltransferase inhibitors.

Original languageEnglish
Pages (from-to)3426-3431
Number of pages6
JournalThe Journal of Organic Chemistry
Volume57
Issue number12
DOIs
Publication statusPublished - 1 Jun 1992

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