Hussain, Rohanah Binte; (1992) Synthesis and structural elucidation of novel highly lipophilic c.n.s. and antiviral drugs. Doctoral thesis (Ph.D.), University College London.

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Abstract

ABSTRACT Many active drugs are restricted in their use pharmacologically due to their poor absorption. This dissertation deals with 2 different families of important drugs, the (i) C.N.S. (ii) antiviral compounds. The lipidic amino acids and their oligomers have a potential use as a novel drug delivery system. Because of their bifunctional nature, they have the capacity to be chemically conjugated to different drugs with a wide variety of functional groups. The resulting conjugates may be either biologically stable or possess biological or chemical instability (the conjugates are prodrugs) and could possess a high degree of membrane-like character, sufficient to facilitate their passage across different membranes. The long hydrocarbon chain of this system, may also have an additional effect of protecting a labile parent drug from enzymatic attack and hence increase the metabolic stability. This lipidic system was synthesised and to vary the physico-chemical properties, the unsubstituted and side chain substituted oligomers and copolymers substituted with highly hydrophilic compounds were also prepared. The important neurotransmitter GABA does not cross the blood brain barrier. Coupling the lipophilic delivery system to GABA, conjugates of differing lipophilicities were synthesised in an attempt to increase the brain uptake. Two types of GABA conjugates were prepared involving ester and amide linkages. In order to carry out the biological in vivo examinations, tritiated and [14C]-GABA conjugates were also prepared. In vitro studies were performed on the unlabelled GABA analogues. Ester conjugates of baclofen have also been used for pharmacological assessment. The second part of the thesis deals with important antiviral compounds. To investigate the chemistry and the physico-chemistry of adenosine conjugates, compounds with ester linkage were synthesised. Finally the research was expanded to the preparation of AZT conjugates. One of the most important clinically approved drug for treating AIDS is 3’-azido-3’- deoxythymidine (AZT). Inadequate inhibition of virus production by macrophages may be the reason for failure to clear infectious virus. To direct larger amounts of the antiretroviral nucleosides to these cells, a major reservoir of HIV, lipidic amino acid and oligomer ester conjugates of AZT were synthesised by utilising the 5’-OH group of AZT for conjugation. To further examine the effect of chemical modification on the pharmacological activity, the 5’-hydroxyl of the AZT was also replaced with a thio group.

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