Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.730801
Title: Analogues of BH4 and nitric oxide synthase activators
Author: Akbar, Muhammad Naveed
ISNI:       0000 0004 6499 6783
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2017
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Abstract:
Nitric oxide synthase (NOS) is an enzyme that catalyses the synthesis of nitric oxide (NO)from L-arginine. There are three kinds of nitric oxide synthase enzymes: neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). Nitric oxide is a biological messenger molecule and a potent vasodilator which controls many biological processes, such as hypertension, stroke, memory, learning disorders and many more. The Nobel Prize in Physiology and Medicine was granted for the discovery and identification of the endothelium-derived relaxing factor as nitric oxide. 5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthases (NOSs) and presumably is present in every cell or tissue of higher organisms. Oxidation of BH4, in diabetes and in different chronic vasoinflammatory diseases can produce cofactor deficiency. This decreased level of BH4 can result in uncoupling of endothelial nitric oxide synthase where this enzyme produces superoxide and thus nitric oxide production is suppressed. BH4 in its active, reduced form is highly unstable and therefore not suitable for oral administration. BH4 does not readily pass across the blood brain barrier; also it cannot be utilized to improve the central neurotransmitter insufficiency in case of BH4 deficiency. This defect of BH4 owes to its hydrophilic nature; however, lipophilic particles can readily pass this brain barrier. If we can have a molecule that is not easily oxidized, and is more lipophilic so that it can cross the blood brain barrier and is also a nitric oxide synthase activator, we can treat all diseases which are caused due to deficiency of nitric oxide especially in old age, when the body starts producing less of nitric oxide. In other words, we can find a cure for diseases which are caused by nitric oxide deficiency. When I started my PhD, Prof Suckling group has already discovered an active pteridine called as WSG1002 1.2 which is more stable to oxidation and has greater solubility than BH41.1. It was an improvement but still not an ideal molecule; both stability and solubility needed to improve. We worked to develop an oxidatively stable and lipophilic pteridine molecule which can act as a cofactor for nitric oxide synthase (NOS) and can correct BH4 deficiency in selected diseases. The following substitutions at WSG1002 (1.2) were considered for my research project. i) N8-deaza ii) C6-unsubstituted iii) 2H at C7 instead of methyl groups. iv) At C6 methyl, hydroxymethyl, acetoxymethyl, acetyl and 1, 2-dihydroxypropyl. This research project provided 8-alkyl and 8-deaza analogues for for nitric oxide synthase enzyme essay, the biological assays for these compounds will be discussed Chapter 3. The investigation of these compounds also made possible studies of the mechanism of action of NOS. Chapter 1 describes nitric oxide and how it is formed from NOS enzymes along with NOS structures and mechanism. It also describes the role of BH4 and its drawbacks. The stucture of the cofactor plays an important role for binding and NOS activity which has been discussed with examples along with requirements for a better molecule. Chapter 2 is about synthesis of important molecules which can help us to understand the mechanism of NO formation and the possibility of finding an ideal drug with better medicinal properties. Although the reactions were challenging, we have prepared many new molecules, many them have been evaluated, and some of them were found to be active and oxidatively stable which is one of the problems with these molecules. 8-Alkyl and 8-deaza analogues have been successfully synthesized. Chapter 3 describes biological results of our compounds which were screened for nitric oxide synthase assays in collaboration with Dr. Simon Daff at the University of Edinburgh. In addition to NOS activity, a number of molecues were also submitted for antibacterial and microbial activity in SIPBS and some of them were found to be active. Chapter 4 describes the experiments for the synthesis of our desired compounds. The methods for the preparation and their characterisation have been given in detail. The last Chapter lists the references.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.730801  DOI: Not available
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