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Synthesis and evaluation of novel anti H.I.V. nucleotides

Nickson, Caleb; (1991) Synthesis and evaluation of novel anti H.I.V. nucleotides. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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A wide variety of nucleosides have been shown to inhibit human immunodeficiency virus (HIV) which is generally believed to be the causative agent of the disease acquired immunodeficiency syndrome (AIDS). In order to have activity these nucleosides are reported to act as their corresponding 5'-triphosphates, which inhibit reverse-transcriptase (RT), a unique viral enzyme. The phosphorylations are catalysed by cellular kinases. This thesis describes the synthesis of a number of nucleoside-5'-phosphate triesters along with the results of biological evaluation studies in two different systems. Water, growth medium and plasma stability studies of selected compounds are also reported. It was hoped that these phosphate triesters could act as pro-drugs of the corresponding nucleoside 5'-monophosphates. A group of 2-hydroxyacetamides was synthesised in a two step procedure from chloroacetyl chloride and the corresponding amine. The 2-hydroxyacetamides, halogenated alcohols, hydroxycarboxylic esters and other unsaturated alcohols were reacted with phosphoryl chlorides to produce a variety of, mainly novel, phosphorochloridates. Among some prepared nucleosides; 3'-Azido-3'-deoxythymidine. 3'-O-methylthymidine, 3'-O-acetylthymidine, 3'-?-O.-methanesulphonylthymidine, also thymidine and 2',3'-dideoxycytidine, were reacted with the phosphorylating reagents to give, in most case the required nucleotide products. Attempts to make 3'-modified nucleoside 5'-phosphonates did not succeed although characterisable products were obtained. Attempted synthesis of 3'-azido-3'-deoxythymidine-5'-di(S-methyllactyl)phosphite gave an H-phosphonate nucleotide product on isolation, however in situ the product could be converted to the phosphate by dinitrogen tetroxide. Thymidine-5'-bis(2,2,2-trichloroethyl)phosphate was reacted with a number of acylating reagents to yield 3'-modified nucleotide products. Biological evaluation of these nucleotides showed some of the compounds to have E.D.50's in the nM region with no toxicity observed at 100 μM. Further testing of the most active compounds by other laboratories using different test systems showed some of the compounds to have therapeutic ratios of over 10,000. Structure activity relationships are discussed. Some of the biologically active compounds showed instability in growth medium and plasma studies though the initial products of decomposition were not free nucleosides. The product from one plasma study was purified and identified as the carboxyl de-esterified nucleoside phosphate triester. The mechanism of action of the compounds is not known though they may act as intracellular sources of nucleotide monophosphate.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Synthesis and evaluation of novel anti H.I.V. nucleotides
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10123957
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