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Synthesis and evaluation of some novel nucleotide derivatives as potential anti-AIDS drugs.

Nicholls, S. R.; (1990) Synthesis and evaluation of some novel nucleotide derivatives as potential anti-AIDS drugs. Doctoral thesis (Ph.D.), University College London. Green open access

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Abstract

Many nucleoside analogues are known to inhibit human immunodeficiency virus (HIV), the causative agent of the disease acquired immunodeficiency syndrome (AIDS). In order to act these nucleosides must be phosphorylated to their corresponding 5'-triphosphates, which can then inhibit reverse-transcriptase (RT), a key viral enzyme. These phosphorylations are catalysed by cellular kinases. The synthesis of a number of nucleoside 5'-dialkyl phosphates is described in this thesis, along with the results of the biological evaluation of some of these derivatives against HIV. It was thought that the 5'-dialkyl phosphates might have been able to act as prodrugs for the corresponding 5'-monophosphates. Firstly the synthesis of 5'-dialkyl phosphates of 3'-0-mesylthymidine, 3'-0-acetylthymidine and 3'-0-ethylthymidine is described, along with the synthesis of some 5'-dialkyl phosphates of 3'-azido-3'-deoxythymidine, 2',3'-dideoxycytidine and 2',3'-dideoxyadenosine. However, when tested, all of the above 5'-dialkyl phosphates were found to be inactive against HIV in vitro. It was thought that this inactivity arose from the metabolic stability of the simple dialkyl esterifying groups present in these compounds. With this in mind some nucleoside 5'-bis(2,2,2-trihaloethyl) phosphate derivatives were synthesised as it was hoped that 2,2,2- trihaloethyl groups would be more labile than simple alkyl ones. Both 3'-azido-3'-deoxythymidine 5'-bis(2,2,2-trifluoroethyl) phosphate and 3'-azido-3'-deoxythymidine 5'-bis(2,2,2-trichloroethyl) phosphate were found to be inhibitors of HIV in vitro. In view of these results, the synthesis of some 5'-bis(2,2,2-trihaloethyl) phosphate derivatives of 2',3'-dideoxycytidine and 3'-fluoro-3'-deoxythymidine was undertaken. The synthesis of some mixed 5'-(alkyl 2,2,2-trihaloethyl) phosphate derivatives of 3'-azido-3'-deoxythymidine was also carried out. The 5'-bis(2,2,2-trichloroethyl) phosphates of 3'-0-mesylthymidine, 3'-0-acetylthymidine, 3'-0-ethylthymidine and 3'-amino-3'-deoxythymidine were also synthesised. As 3'-azido-3'-deoxythymidine 5'-bis(2,2,2-trichloroethyl) phosphate was able to inhibit HIV in vitro, the 5'-bis(2-chloroethyl) phosphate and the 5'-bis(2,2-dichloroethyl) phosphate of 3'-azido-3'-deoxythymidine were prepared, in order to ascertain if these compounds were able to inhibit HIV also. The 5'-bis(2-chloroethyl) phosphate of 3'-azido- 3'-deoxythymidine does indeed display activity against HIV in vitro. An attempt was made to synthesise a thymidine 5'-dialkyl phosphonate species, by a Michaelis-Arbuzov type reaction between 5'-bromo-5'-deoxythymidine and diethyl phosphite. However, it was only possible to isolate a 3'-hydrogenphosphate species from this reaction. As the method by which 3'-azido-3'-deoxythymidine 5'-bis(2,2,2-trichloroethyl) phosphate acts as an inhibitor of HIV probably involves the hydrolysis of the phosphate moiety to either the 5'-monophosphate or the parent nucleoside, some studies on the hydrolysis of 3'-azido-3'-deoxythymidine 5'-bis(2,2,2-trichloroethyl) phosphate at a variety of pH were carried out.

Type: Thesis (Doctoral)
Qualification: Ph.D.
Title: Synthesis and evaluation of some novel nucleotide derivatives as potential anti-AIDS drugs.
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/10124121
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