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.
Export Options
About this article
Cite this article as:
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 |
Call for Papers in Thematic Issues
Carbohydrates in Computational and Medicinal Chemistry
Carbohydrates are the most essential organic molecules and are involved in the maintenance of various physiological and metabolic processes in living organisms. Carbohydrate-based compounds have come to the attention of researchers because of their significant contributions to biological functions, such as cell development and cell proliferation, connections between several cells, ...read more
Recent Advances in the Medicinal Chemistry of Cancer
Scope of the Thematic Issue: Correlation between structure and function is one of the important aspects of the success of anti-cancer compounds associated with their structure-activity interactions, physiology, biochemical, molecular, and genetic processes. Overcoming these obstacles is key to obtaining further insights into developments in rational drug design, bioorganic chemistry, ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Role of Sympathetic Nerve Activity in Obesity, Hypertension and Metabolic Syndrome
Current Hypertension Reviews Change in INSR, APBA2 and IDE Gene Expressions in Brains of Alzheimer's Disease Patients
Current Alzheimer Research Literature Review: Use of Family History for Primary Paediatric Care as the Next Step Towards use of Genomics in Healthcare
Current Pediatric Reviews A Scientometrics Analysis and Visualization of Depressive Disorder
Current Neuropharmacology PPARγ Activation Improves the Molecular and Functional Components of Ito Remodeling by Angiotensin II
Current Pharmaceutical Design Roles of Orexin in Regulation of Energy Homeostasis
Current Medicinal Chemistry - Central Nervous System Agents Novel Role of NPC1L1 in the Regulation of Hepatic Metabolism: Potential Contribution of Ezetimibe in NAFLD/NASH Treatment
Current Vascular Pharmacology Gliclazide, Inflammation and Atherosclerosis
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Peroxisome Proliferator-Activated Receptor (PPAR)β /δ: A New Potential Therapeutic Target for the Treatment of Metabolic Syndrome
Current Molecular Pharmacology Carotid and Vertebral Arterial Variations in Alzheimer's Disease
Current Alzheimer Research Risk Factors for Suicide – An Alternative View
CNS & Neurological Disorders - Drug Targets In Vitro Models of Human T Cell Development: Dishing Out Progenitor T Cells
Current Immunology Reviews (Discontinued) Effect of Cardioembolic Etiology on Intravenous Thrombolysis Efficacy for Acute Ischemic Stroke
Current Neurovascular Research Cardiovascular Disease in Diabetes
Mini-Reviews in Medicinal Chemistry Heart Failure in South America
Current Cardiology Reviews Age-Related Changes in Adult Muscle Morphology
Current Aging Science Aspartic Proteinases in Disease: A Structural Perspective
Current Drug Targets One-pot Synthesis and its Practical Application in Pharmaceutical Industry
Current Organic Synthesis Hyperfibrinogenemia is Significantly Associated with an Increased Risk of In-hospital Mortality in Acute Ischemic Stroke Patients
Current Neurovascular Research Regenerative Therapies for Improving Myocardial Perfusion in Patients with Cardiovascular Disease: Failure to Meet Expectations but Optimism for the Future
Current Vascular Pharmacology