Asymmetric Synthesis of Conformationally Restricted l-Arginine Analogues as Active Site Probes of Nitric Oxide Synthase

• Published in: Journal of organic chemistry Vol. 64; no. 10; pp. 3467 - 3475
• Main Authors: Atkinson, Robert N, Moore, Lisa, Tobin, Joseph, King, S. Bruce
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.05.1999; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; SELECTIVE-INHIBITION; OXIDATION; AMINO-ACID; PTERIN; REDUCTION; SUBSTRATE; DERIVATIVES; BRAIN
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo982161f

Using the catalytic asymmetric Sharpless carbamate aminohydroxylation, conformationally restricted l-arginine and l-homoarginine derivatives (5 − 8) were prepared in good enantiomeric excess to investigate the binding requirements of l-arginine-based compounds with nitric oxide synthase. The l-arginine derivatives (5 and 6) inhibited both the inducible and neuronal isoforms of nitric oxide synthase with little isoform selectivity (5, IC50 = 42 and 144 μM, 6, 8 and 12 μM, respectively). The guanidine-containing compound (5) did not act as a nitric oxide producing substrate for nitric oxide synthase. The ability of these compounds to interact with the enzyme supports the idea that l-arginine-based inhibitors bind to the enzyme in a folded conformation. The l-homoarginine derivatives (7 and 8) did not interact with the enzyme as either substrates or inhibitors. The two-carbon l-arginine homologue (9), prepared from l-phenylalanine, demonstrated the greatest isoform selective inhibition of the compounds examined (IC50(iNOS) = 19 and IC50(nNOS) = 147 μM, IC50(nNOS)/IC50i(NOS) = 7.7). These results suggest isoform selective inhibition may be related to the folded conformations required for binding of these higher l-arginine homologues.