Publications

Abstract Acyclic nucleotide analogs derived from antiviral 9-(2-phosphonylmethoxyethyl)adenine by modification at the side chain or by alternation of the heterocyclic base were synthesized and investigated for their antiviral activity.

Abstract Compound 15 – the 2′‐azido analog of the anti‐HIV compound 2′,3′‐didehydro‐2′,3′‐dideoxythymidine – was synthesized. Treatment of 5′‐ O ‐trityl‐β‐ D ‐ribofuranosylthymine ( 1 ) with DAST or MSTF gave the 2,2′‐anhydro derivative 2 . The latter and its 3′‐ O ‐benzoate 3 were used for the synthesis of the 2′‐azido‐2′‐deoxy derivatives 4 and 5 . Two routes to the synthesis of 15 from 5 were investigated. (i) Treatment of 5 with DAST gave a mixture of the 5′‐ O ‐trityl derivatives 12 and 13 as well as 1‐(2‐azido‐2,3‐dideoxy‐3‐fluoro‐β‐ D ‐xylofuranosyl)thymine ( 16 ) along with 2,3′‐anhydro derivative 14 (2%). Detritylation of the mixture yielded 15 (39%) and 16 (12%). (ii) Mesylation of 5 gave 17 which yielded 15 upon saponification and detritylation. Compound 15 showed moderate inhibitory activity against HIV‐1 and HIV‐2 in MT‐4 cells.

We have recently reported the discovery of an entirely new category of potent antiviral agents based on novel deoxynucleoside analogues with unusual fluorescent bicyclic furano base moieties. In order to probe structure activity relationships we prepared a series of 5-aryl derivatives of the lead structures. We herein report the synthesis, characterization, and antiviral evaluation of these novel compounds. 5-Aryl derivatives of the parent nucleosides were synthesized from the corresponding alkynyl deoxyuridines using a simple, versatile and efficient one-step conversion, based on a palladium-catalysed cyclization. As previously noted for the lead compounds, a long alkyl side-chain on the base moiety is essential for antiviral activity. Even with the optimal (C8-C10) side-chain, most of the present compounds are markedly less active than their parent structures. However, some of the synthesized compounds still retained antiviral activity at non-cytotoxic concentrations, being only two- to fivefold less active than the current clinical agent acyclovir. Possible reasons for this structure activity relationship are discussed.

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