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 pote nt antivaricella-zoster virus agents based on novel deoxynucleoside analogu es bearing unusual fluorescent bicyclic furo base moieties, Initial studies revealed an absolute requirement of a long alkyl side-chain, with an optim al length of C8-C10, for antiviral activity. However. the impact of this re quirement on the physical properties of these compounds is high: inherent l ipophilicity 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-cha ins, designed to improve the aqueous solubility of the compounds. Synthesis of target nucleosides involved Pd-catalysed coupling of terminal alkynes w ith 5-iodo-2'-deoxyuridine. The 5-alkynyl nucleosides thus obtained were th en treated with copper (I) iodide to produce the desired bicyclic analogues . As anticipated, the new compounds exhibited a dramatic increase in aqueou s solubility, although antiviral activity was significantly reduced. A poss ible correlation between antiviral activity and overall compound lipophilic ity is discussed.