Inhibition of long chain fatty acyl-CoA synthetase (ACSL) and ischemia reperfusion injury.
Various triacsin C analogs, containing different alkenyl chains and carboxylic acid bioisoteres including 4-aminobenzoic acid, isothiazolidine dioxide, hydroxylamine, hydroxytriazene, and oxadiazolidine dione, were synthesized and their inhibitions of long chain fatty acyl-CoA synthetase (ACSL) were examined. Two methods, a cell-based assay of ACSL activity and an in situ [(14)C]-palmitate incorporation into extractable lipids were used to study the inhibition. Using an in vivo leukocyte recruitment inhibition protocol, the translocation of one or more cell adhesion molecules from the cytoplasm to the plasma membrane on either the endothelium or leukocyte or both was inhibited by inhibitors 1, 9, and triacsin C. The results suggest that inhibition of ACSL may attenuate the vascular inflammatory component associated with ischemia reperfusion injury and lead to a decrease of infarct expansion.
Department of Chemistry, 213 CBC Building, Kansas State University, Manhattan, KS 66506, United States.
Allan M
AM
Prior
Department of Chemistry, 213 CBC Building, Kansas State University, Manhattan, KS 66506, United States.
Man
M
Zhang
Department of Biomedical Sciences, Vascular Drug Research Center, School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, TX 79106, United States.
Nina
N
Blakeman
Department of Biomedical Sciences, Vascular Drug Research Center, School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, TX 79106, United States.
Palika
P
Datta
Department of Pathology, Microbiology, Immunology and Forensic Medicine, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, United States.
Hung
H
Pham
Department of Pathology, Microbiology, Immunology and Forensic Medicine, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, United States.
Qian
Q
Chen
Department of Pathology, Microbiology, Immunology and Forensic Medicine, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, United States.
Lindon H
LH
Young
Department of Biomedical Sciences, Vascular Drug Research Center, School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, TX 79106, United States. Electronic address: Margaret.Weis@ttuhsc.edu.
Margaret T
MT
Weis
Department of Chemistry, 213 CBC Building, Kansas State University, Manhattan, KS 66506, United States. Electronic address: duy@ksu.edu.
Duy H
DH
Hua
D000818:Animals; D002460:Cell Line; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D013329:Structure-Activity Relationship; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
D004791:Enzyme Inhibitors; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
Hydroxytriazene; Ischemia reperfusion injury; Long chain fatty acyl-CoA synthetase (ACSL) inhibitors; Oxadiazolidine dione; Triacsin C