TY - JOUR
T1 - Syntheses, Structures, and Enzymatic Evaluations of Hemiacylcarnitiniums, a New Class of Carnitine Acyltransferase Inhibitors
AU - Gandour, Richard D.
AU - Blackwell, Noelle L.
AU - Colucci, William J.
AU - Chung, Chang
AU - Bieber, Loran L.
AU - Ramsay, Rona R.
AU - Brass, Eric P.
AU - Fronczek, Frank R.
PY - 1992/6/1
Y1 - 1992/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0026639378&partnerID=8YFLogxK
U2 - 10.1021/jo00038a035
DO - 10.1021/jo00038a035
M3 - Article
AN - SCOPUS:0026639378
SN - 0022-3263
VL - 57
SP - 3426
EP - 3431
JO - The Journal of Organic Chemistry
JF - The Journal of Organic Chemistry
IS - 12
ER -