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Title: The synthesis and study of novel nitric oxide synthase activators.
Author: Rao, Morthala Raghavendar
Awarding Body: University of Strathclyde, Pure and Applied Chemistry
Current Institution: University of Strathclyde
Date of Award: 2008
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Abstract:
Nitric oxide (NO) is an essential molecule for the maintenance of blood pressure and vascular tone In mammals including humans. NO is produced by three different nitric oxide synthases (NOSs): Neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS). Tetrahydrobiopterin (BH4) 1.1 is one of the important cofactors of these three NOSs: The deficiency of BH4 causes reduced nitric oxide production which in turn contributes to the hypertension, diabetes, oxidative stress etc. Biologists from various groups suggested that the dihydrobiopterin BH2 5.1. is an inhibitor of all three NOSs. However one of our library compounds 1.2 (WSG1002) in BH4 deficient tissues, although in dihydro oxidation state as 5.1, had shown similar action as natural BH4 by producing nitric oxide. Thus. WSG1002 has become lead compound for this PhD study. The main aim of my PhD study was to synthesise different blocked dihydropteridines with variation at positions 2, 6 and 7 in 1.2 to identify a '!lore efficient and selective eNOS activator, and to study the .mechanism behind the unusual activation ofNOSs by these dihydropteridines. Chapter One gives an introduction to the project. In this, a review of nitric oxide synthase enzymes,. mechanism of nitric oxide synthesis and introduction to the pteridines are covered. Chapter Two describes the synthesis of blocked dihydropteridines; most of the discussion is devoted to the challenges faced in the construction of sterically highly demanding a,a-disubstituted amino ketones. After considering various synthetic routes, a highly flexible and divergent synthetic route has been developed. In pursuit of diversity at C2 in pteridi!1e 1.2, a new synthetic route has b~en developed. starting from trichloropyrimidine 3.102. In this a stepwise regioselective nucleophilic substitution of three chlorines In 3.102 has been successful. Consequently a new pteridine 3.110 with variation at C2 was constructed. Chapter Four is dedicated to the asymmetric alkylation of alanine derivative 4.36. This chapter starts with a brief review of enantioselective alkylation of Schiff bases of glycine and alanine esters with variety of phase transfer catalysts. In the results and discussion section, syntheses of the cinchonidine-derived catalyst 4.13 and the usubstituted alanine derivative 2.120 with >99 % ee is discussed in detail. In Chapter Five, the biological results of blocked dihydro and tetrahydropteridines from nNOS assays have been demonstrated. In this project tetrahydropteridines 2.183b and 2.183d have shown excellent activity in nNOS by producing nitric oxide. Chapter Six provides detailed experimental procedures and characterisation data of compounds discussed in chapters from two to five.
Supervisor: Not available Sponsor: Not available
Qualification Name: University of Strathclyde, Pure and Applied Chemistry, 2008 Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.486538  DOI: Not available
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