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Synthesis and anti-varicella-zoster virus activity of some novel bicyclic nucleoside inhibitors: effect of enhanced aqueous solubility

Brancale, Andrea, Srinivasan, Subashini, McGuigan, Christopher, Andrei, Graciela, Snoeck, Robert, De Clercq, Erik and Balzarini, Jan 2000. Synthesis and anti-varicella-zoster virus activity of some novel bicyclic nucleoside inhibitors: effect of enhanced aqueous solubility. Antiviral Chemistry & Chemotherapy 11 (6) , pp. 383-393.

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Abstract

We have recently reported the discovery of an entirely new category of potent antivaricella-zoster virus agents based on novel deoxynucleoside analogues bearing unusual fluorescent bicyclic furo base moieties. Initial studies revealed an absolute requirement of a long alkyl side-chain, with an optimal length of C8-C10, for antiviral activity. However, the impact of this requirement on the physical properties of these compounds is high: inherent lipophilicity and extremely poor aqueous solubility, which may limit the use of these nucleosides as drugs. In order to address this issue, we have now prepared a new series of analogues, bearing ether and glycol type side-chains, designed to improve the aqueous solubility of the compounds. Synthesis of target nucleosides involved Pd-catalysed coupling of terminal alkynes with 5-iodo-2'-deoxyuridine. The 5-alkynyl nucleosides thus obtained were then treated with copper (I) iodide to produce the desired bicyclic analogues. As anticipated, the new compounds exhibited a dramatic increase in aqueous solubility, although antiviral activity was significantly reduced. A possible correlation between antiviral activity and overall compound lipophilicity is discussed.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Healthcare Sciences
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: Antiviral Agents/chemical synthesis; Antiviral Agents/pharmacology; Herpesvirus 3, Human/drug effects; Pyrimidine Nucleosides/antagonists & inhibitors; Pyrimidine Nucleosides/chemical synthesis
Publisher: International Medical Press
ISSN: 0956-3202
Last Modified: 18 Oct 2017 13:44
URI: http://orca-mwe.cf.ac.uk/id/eprint/7483

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