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 Pages 445 - 453 ( 9 )
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.
carnitine palmitoyltransferase, antidiabetic agent, chiral synthesis, enzyme inhibition
Department of Chemistry (MC 0212) Virginia Tech, Blacksburg, VA, USA.