Asymmetric Synthesis of Conformationally Restricted l -Arginine Analogues as Active Site Probes of Nitric Oxide Synthase
| Autor: | King Sb, Atkinson Rn, Tobin J, Moore L |
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| Rok vydání: | 1999 |
| Předmět: | |
| Zdroj: | The Journal of Organic Chemistry. 64:3467-3475 |
| ISSN: | 1520-6904 0022-3263 |
| DOI: | 10.1021/jo982161f |
| Popis: | 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, IC(50) = 42 and 144mgr;M, 6, 8 and 12mgr;M, 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 (IC(50)(iNOS) = 19 and IC(50)(nNOS) = 147mgr;M, IC(50)(nNOS)/IC(50)i(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. |
| Databáze: | OpenAIRE |
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