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

We have recently reported the discovery of an entirely new category of potent anti-varicella-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.