- Heterocyclic analogues of L-citrulline as inhibitors of the isoforms of nitric oxide synthase (NOS) and identification of N(δ)-(4,5-dihydrothiazol-2-yl)ornithine as a potent inhibitor
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L-Thiocitrulline is a known potent inhibitor of several isoforms of nitric oxide synthase (NOS). To explore the structure-activity relationships (SARs) for this molecule in more depth than has previously been reported, three analogues substituted at the sulphur of the isothioureas have been synthesised. In two of these, the S-substituent was 'tied back' sterically by cyclisation to the nitrogen remote from the amino-acid unit. N(δ)-(4,5-Dihydrothiazol-2-yl)ornithine was identified as an inhibitor of rat inducible and constitutive isoforms of NOS and of a constitutive NOS derived from a human tumour xenograft. Analogous N(δ)-(thiazol-2-yl)ornithines were less active, whereas the corresponding N(δ)-(oxazol-2-yl)ornithine and N(δ)-(pyrimidin-2-yl)ornithine failed completely to inhibit NOS. A new efficient preparation of the critical synthetic intermediate, N(α)-Boc-thiocitrulline t-butyl ester, has been developed. Further exploration of the SAR with 2-amino-5-(heterocyclylthio)pentanoic acids (synthesised from 2-(Boc-amino)-5-bromopentanoic acid t-butyl ester), with N-(4-aminobutyl)thiourea and with 2-(4-aminobutylamino)-4,5-dihydrothiazole enabled refinement of our previous model for binding of the substrate, L-arginine, and the inhibitors to NOS.
- Ulhaq, Saraj,Chinje, Edwin C.,Naylor, Matthew A.,Jaffar, Mohammed,Stratford, Ian J.,Threadgill, Michael D.
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p. 1787 - 1796
(2007/10/03)
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- Synthesis of L-thiocitrulline, L-homothiocitrulline, and S-methyl-L- thiocitrulline: A new class of potent nitric oxide synthase inhibitors
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Nitric oxide synthase catalyzes the NADPH- and O2-dependent conversion of L-arginine to L-citrulline and nitric oxide. L-Thiocitrulline, L- homothiocitrulline, and S-methyl-L-thiocitrulline, novel citrulline analogs, have been synthesized and are shown to be potent inhibitors of both the constitutive brain and the inducible smooth muscle isoforms of nitric oxide synthase. Although many N(ω)-monosubstituted arginine derivatives inhibit nitric oxide synthase, inhibitory citrulline derivatives have not previously been reported. S-Methyl-L-thiocitrulline is significantly more potent than N(ω)-methyl-L-arginine, the prototypic nitric oxide synthase inhibitor.
- Narayanan,Griffith
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p. 885 - 887
(2007/10/02)
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- Synthesis of the putative L-arginine metabolite L-N(G)-hydroxyarginine
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Syntheses of L-N(G)-hydroxyarginine (1), the putative biosynthetic precursor of nitric oxide, and the 15N labelled analogs 9 and 10 using L-ornithine as the enantiopure starting material is reported.
- Feldman
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p. 875 - 878
(2007/10/02)
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