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DOI: 10.1039/A900336C (Paper) Reference Section for: J. Chem. Soc., Perkin Trans. 1, 1999, 1039-1050

New modified nucleoside 5′-triphosphates: synthesis, properties towards DNA polymerases, stability in blood serum and antiviral activity

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Alexander V. Shipitsin, Lyubov S. Victorova, Elena A. Shirokova, Natalya B. Dyatkina, Lyudmila E. Goryunova, Robert Sh. Beabealashvilli, Chris J. Hamilton, Stanley M. Roberts and Alexander Krayevsky

Abstract

A series of new nucleoside 5′-triphosphate mimetics, 2, 3, 5, 6, 8–10, modified at the glycone and all three phosphate residues, have been synthesised and studied. These compounds only bear the enzymatically labile anhydride bond between the α and β phosphorus atoms. The preparative chemistry involved the preparation of phosphonic salts 30, 31 and 32 and coupling of these species to the morpholidate 33. The mechanism of formation of some of the intermediates ‘en route’ to 27 and 28 is discussed. All of the target compounds demonstrated high stability in human blood serum with half lives towards hydrolysis of up to 4.5 days. Some of these nucleoside triphosphonates have been shown to be selective inhibitors of DNA synthesis catalysed by retroviral reverse transcriptases and terminal deoxynucleotidyl transferases. They inhibited replication of the artificial virus containing Moloney murine leukemia virus reverse transcriptase in infected cell culture, probably due to the inhibition of a reverse transcription step of a genomic RNA. Compared to the triphosphonates, the corresponding monophosphonates demonstrated decreased antiviral activity by 1–2 orders of magnitude. This implies that the triphosphonates inhibit virus replication directly, rather than by a two-step mechanism based on their hydrolysis to the monophosphonates and subsequent intracellular diphosphorylation. Being totally independent of the enzymatic phosphorylation pathways of the host cell, the compounds under study may also be able to inhibit retrovirus reproduction both in kinase deficient cell lines and in the intercellular blood media.

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