Preparation and evaluation of new l-canavanine derivatives as nitric oxide synthase inhibitors

New derivatives of the amino acid l-canavanine were prepared by total chemical synthesis and evaluated as inhibitors of inducible nitric oxide synthase (NOS). Replacement of the δ-methylene group of known NOS inhibitors with an oxygen atom produced dramatic effects as to the ability of these compoun...

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Bibliographic Details
Published inTetrahedron Vol. 57; no. 30; pp. 6557 - 6565
Main Authors Li, Xiaofeng, Atkinson, Robert N, Bruce King, S
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier Ltd 23.07.2001
Elsevier
Subjects
Chemistry
Chemistry, Organic
inhibitors
l-canavanine
nitric oxide synthases
Physical Sciences
Science & Technology
l-canavanine
nitric oxide synthases
inhibitors
RESTRICTED ARGININE ANALOGS
SELECTIVE-INHIBITION
DOMAIN
L-canavanine
METHYL-L-THIOCITRULLINE
POTENT
PTERIN
DIMER
SUBSTRATE
BINDING
PARADIGM
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Summary:New derivatives of the amino acid l-canavanine were prepared by total chemical synthesis and evaluated as inhibitors of inducible nitric oxide synthase (NOS). Replacement of the δ-methylene group of known NOS inhibitors with an oxygen atom produced dramatic effects as to the ability of these compounds to interact with the enzyme. These results indicate that the addition of an electron withdrawing group in the side chain of l-arginine-derived NOS inhibitors must be considered during inhibitor design depending on the expected mode of interaction with the enzyme. The preparation and evaluation of compounds 15 and 16 as NOS inhibitors is described.
ISSN:0040-4020
1464-5416
DOI:10.1016/S0040-4020(01)00547-6