Abstract
The syntheses of (R)- and (S)-norcarnitine ethyl esters are described starting with an optimized, chiral chemical reduction of ethyl 4-chloroacetoacetate followed by azide substitution, reduction, and dimethylation. The reaction of (R)- and (S)-norcarnitine ethyl esters with 1-bromoheptadecan-2-one gives (+)- and (-)-6-[(methoxycarbonyl)methyl]-2- pentadecyl-4,4-dimethylmorpholinium bromide, respectively, which hydrolyzes to (+)- and (-)-6-(carboxylatomethyl)-2- pentadecyl-4,4-dimethylmorpholinium (hemipalmitoylcarnitinium, (+)- and (-)-HPC), respectively, upon treatment with a hydroxide resin. (+)- and (-)-HPC are reversible active-site directed inhibitors of hepatic mitochondrial CPTs. Both stereoisomers inhibit CPT I and CPT II in control and streptozotocin diabetic rat to the same extent (Imax = 100%). Using intact mitochondria (CPT I), I50 values for (-)-HPC and (+)-HPC were 15.5 μM and 47.5 μM, respectively. The I50 values for CPT II were 6.7 μM and 38.5 μM for (-)-HPC and (+)-HPC, respectively. The mode of inhibition was uncompetitive for CPT I with respect to acyl-CoA. The apparent Ki for (-)-HPC is about 5 μM. These data suggest that (-)-HPC may be useful for further evaluation as an antidiabetic agent.
Keywords: carnitine palmitoyltransferase, antidiabetic agent, chiral synthesis, enzyme inhibition
Medicinal Chemistry
Title: Comparison of (+)- and (-)-Hemipalmitoylcarnitinium as Inhibitors of Hepatic Mitochondrial Carnitine Palmitoyltransferases in Diabetic Rats
Volume: 1 Issue: 5
Author(s): P. S. Savle, N. E. Neptune, Y. Yang, J. H. Rouden, B. L. Kite, E. W. Sugandhi, R. V. Macri, K. Kashfi and R. D. Gandour
Affiliation:
Keywords: carnitine palmitoyltransferase, antidiabetic agent, chiral synthesis, enzyme inhibition
Abstract: The syntheses of (R)- and (S)-norcarnitine ethyl esters are described starting with an optimized, chiral chemical reduction of ethyl 4-chloroacetoacetate followed by azide substitution, reduction, and dimethylation. The reaction of (R)- and (S)-norcarnitine ethyl esters with 1-bromoheptadecan-2-one gives (+)- and (-)-6-[(methoxycarbonyl)methyl]-2- pentadecyl-4,4-dimethylmorpholinium bromide, respectively, which hydrolyzes to (+)- and (-)-6-(carboxylatomethyl)-2- pentadecyl-4,4-dimethylmorpholinium (hemipalmitoylcarnitinium, (+)- and (-)-HPC), respectively, upon treatment with a hydroxide resin. (+)- and (-)-HPC are reversible active-site directed inhibitors of hepatic mitochondrial CPTs. Both stereoisomers inhibit CPT I and CPT II in control and streptozotocin diabetic rat to the same extent (Imax = 100%). Using intact mitochondria (CPT I), I50 values for (-)-HPC and (+)-HPC were 15.5 μM and 47.5 μM, respectively. The I50 values for CPT II were 6.7 μM and 38.5 μM for (-)-HPC and (+)-HPC, respectively. The mode of inhibition was uncompetitive for CPT I with respect to acyl-CoA. The apparent Ki for (-)-HPC is about 5 μM. These data suggest that (-)-HPC may be useful for further evaluation as an antidiabetic agent.
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Savle S. P., Neptune E. N., Yang Y., Rouden H. J., Kite L. B., Sugandhi W. E., Macri V. R., Kashfi K. and Gandour D. R., Comparison of (+)- and (-)-Hemipalmitoylcarnitinium as Inhibitors of Hepatic Mitochondrial Carnitine Palmitoyltransferases in Diabetic Rats, Medicinal Chemistry 2005; 1 (5) . https://dx.doi.org/10.2174/1573406054864115
DOI https://dx.doi.org/10.2174/1573406054864115 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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