Design and synthesis of some novel masked 5'-N-substituted thymidine nucleotides as anti-HIV agents

Turner, Stephen John (1994) Design and synthesis of some novel masked 5'-N-substituted thymidine nucleotides as anti-HIV agents. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

This project describes the synthesis of some novel alkyl and aryl masked nucleotides of thymidine and some of its analogues, with a nitrogen atom substituted for the oxygen within the nucleoside to phosphorus linkage. These compounds were prepared by use of phosphorochloridate chemistry and the reaction between an azide and a phosphite to yield a phosphoramidate (Staudinger reaction). Both methods yielded the desired products in good yields, side products caused by diphosphorylation and migration of an alkyl group onto the thymine base respectively were also isolated. The products were designed to act as modified membrane soluble prodrugs of the bio-active free nucleotide, but they did not exhibit significant anti-HIV activity upon in vitro analysis. Modification of the 3'-hydroxyl group of thymidine by acylation and mesylation, and synthesis of 5'-phosphoramide proton substituted analogues failed to demonstrate an increase in biological activity.

Attempts to protect the 5'-phosphoramide proton by a 1,3-migration of an alkyl group during the Staudinger reaction by reacting a series of phosphites with 5'-amino-2,3'-anhydrothymidine only yielded the desired product using trimethylphosphite. The masked 5'-amino-2,3'-anhydrothymidine nucleotides isolated were reacted with sodium hydride to give the 5'-amino-masked nucleotides of 3'-deoxy-2',3'-didehydrothymidine. Nucleophilic attack of an azide onto the 2,3'-anhydro-linkage gave a 5'-amino-masked nucleotide of 3'-azidothymidine. Use of phosphorochloridate chemistry was also used to yield this product.

A more synthetically useful procedure for the preparation of the masked 5'-amino-3'-deoxy-2',3'-didehydrothymidine analogues involved the reaction of 5'-azido-3'-deoxy-2',3'-didehydrothymidine with an appropriate phosphite.

Biological evaluation of these analogues indicated that their anti-HIV activity was several orders of magnitude lower than that observed for the nucleoside analogue reference 3'-azidothymidine (AZT). This indicates that the 5'-N-modified nucleotide analogues prepared are not potent inhibitors of the replication of HIV.

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