Heme-coordinating analogs of lauric acid as inhibitors of fatty acid omega-hydroxylation.
A series of omega-substituted fatty acids with potential heme-coordinating groups was synthesized as inhibitors of lauric acid omega-hydroxylation. The compounds were evaluated using liver microsomes from clofibrate (CF)-induced rats and an engineered expressed CYP4A1-derived fusion protein called f4A1. omega-Imidazolyl-decanoic acid (compound 11) and omega-aminolauric acid (compound 7) were potent Type II ligands and potent inhibitors of lauric acid omega-hydroxylation in both CF-microsomes and f4A1. Replacing their terminal amino or imidazolyl groups with other potential iron-binding groups such as omega-methylsulfinyl-, omega-cyano-, omega-azido-, or omega-formamido all greatly reduced their potency as inhibitors of omega-hydroxylation and their affinity for cytochrome P450 as measured by Ks values. In CF-microsomes, inhibition of (omega-1)-hydroxylation of lauric acid by a homologous series of omega-imidazolyl-alkanoic acids varied only 2-fold but in the same incubations inhibition of omega-hydroxylation increased 22-fold upon going from C-8 to C-12. A similar dependence of binding affinity and inhibitory potency on chain length was also seen in the f4A1 system. In contrast, chain length had little effect on activity among n-alkylamines or N-alkylimidazoles lacking a carboxyl or other polar functional group, suggesting that 7, 11, and related bifunctional compounds interact with CYP4A1 in CF-microsomes and with f4A1 in a specific bidentate fashion. Imidazoles containing phenyl, benzyl, or phenylethyl substituents at N-1 interact less strongly than related N-alkyl-imidazoles of similar carbon number and hydrophobicity, suggesting that the steric bulk and/or rigidity of the phenyl ring is not well accommodated in the active site.
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Department of Medicinal Chemistry, University of Kansas, Lawrence 66045-2506, USA.
Alterman
M A
MA
Chaurasia
C S
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Bambal
R B
RB
Hanzlik
R P
RP
D000818:Animals; D002994:Clofibrate / Q000494:pharmacology; D042926:Cytochrome P-450 CYP4A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006418:Heme / Q000737:chemistry; D007850:Lauric Acids / Q000737:chemistry*; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007850:Lauric Acids; D011993:Recombinant Fusion Proteins; C030358:lauric acid; D006418:Heme; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; D002994:Clofibrate