Synthesis and evaluation of new sulfur-containing L-arginine-derived inhibitors of nitric oxide synthase.
A series of compounds (7, 8, 10-17, 23) containing new functional groups derived by the combination of the substrate, intermediate, product, and known inhibitors of nitric oxide synthase (NOS) were prepared and evaluated against NOS. While none of the compounds assayed acted as a nitric oxide-producing substrate, the sulfur-containing arginine derivatives 10-12 were competitive inhibitors of iNOS with Ki's of 202, 7, and 58 microM, respectively. Compound 11 demonstrated the greatest potency against NOS-mediated citrulline formation for each of the three isoforms with IC50's of 6. 7, 19.7, and 13 microM for nNOS, eNOS, and iNOS, respectively. Compounds 10-12 each demonstrated a slight selectivity for inhibition of the neuronal isoform compared to the endothelial and inducible isoforms. These compounds also influenced the NADPH oxidase activity and heme iron spin state in a manner similar to structurally related compounds. Compound 10, a thiocarbonyl-containing compound, decreased the NADPH oxidase activity of the enzyme (EC50 = 190 microM) and shifted the heme iron spin state toward a low-spin configuration, similar to that of L-thiocitrulline. Compounds 11 and 12, S-alkylthiocitrulline derivatives, decreased the NADPH oxidase activity of the enzyme (EC50 = 6.6 and 180 microM, respectively) and shifted the heme iron spin state toward a high-spin configuration, similar to that of L-S-methylisothiocitrulline. Carbonyl-containing amino acid (7, 8, 23) and non-amino acid (13-17) analogues did not interact well with the enzyme.
Ichimori
K
K
Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, USA.
Stuehr
D J
DJ
Atkinson
R N
RN
King
S B
SB
D001120:Arginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D002956:Citrulline / Q000138:chemical synthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006418:Heme / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D019255:NADPH Oxidases / Q000737:chemistry; D009474:Neurons / Q000201:enzymology; D009569:Nitric Oxide / Q000138:chemical synthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D002956:Citrulline; D009569:Nitric Oxide; D006418:Heme; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases