The journey towards elucidating the anti-HCMV activity of alkylated bicyclic furano pyrimidines.

Bicyclic furanopyrimidines were recently discovered by us to be potent and selective inhibitors of VZV. Related studies to investigate the role of the sugar in this activity uncovered dideoxy furanopyrimidines as inhibitors of HCMV and this led to the preparation of highly modified long alkyl chain furanopyrimidines from the N- and O-alkylation of their parent bases. Herein we describe their synthesis and subsequent biological evaluation against HCMV.

Synthesis and antiviral evaluation of some 3'-fluoro bicyclic nucleoside analogues.

The synthesis of 3'-fluoro analogues of recently discovered highly potent anti-VZV furanopyrimidine deoxynucleosides (BCNAs) is herein reported, for both the alkyl and alkylphenyl series. The compounds are tested against a range of herpes viruses and display poor activity, strongly supporting the notion of the importance of the presence of a 3'-OH for antiviral activity.

Bicyclic nucleoside inhibitors of varicella-zoster virus (VZV): Pd-catalysed synthesis of 5-aryl derivatives and their biological evaluation.

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.

Bicyclic nucleoside inhibitors of varicella-zoster virus: effect of terminal aryl substitution in the side-chain.

We have previously reported the discovery and preliminary structure-activity relationships of a new class of inhibitors of varicella-zoster virus (VZV). These novel furanopyrimidine nucleosides bear unusual bicyclic base moieties and exhibit complete specificity for VZV. Limited in vitro cytotoxicity has been detected and the bicyclic nucleosides are now well established as a new family of potent antivirals.

Lack of susceptibility of bicyclic nucleoside analogs, highly potent inhibitors of varicella-zoster virus, to the catabolic action of thymidine phosphorylase and dihydropyrimidine dehydrogenase.

The susceptibility of the bicyclic nucleoside analogs (BCNAs), highly potent and selective inhibitors of varicella-zoster virus (VZV), to the enzymes involved in nucleoside/nucleobase catabolism has been investigated in comparison with the established anti-VZV agent (E)-5-(2-bromovinyl)-2'-deoxyuridine [BVDU; brivudine (Zostex)]. Whereas human and bacterial thymidine phosphorylases (TPases) efficiently converted BVDU to its antivirally inactive free base (E)-5-(2-bromovinyl)uracil (BVU), BCNAs showed no evidence of conversion to the free base in the presence of these enzymes. The lack of substrate affinity of TPase for the BCNAs could be rationalized by computer-assisted molecular modeling of the BCNAs in the TPase active site.

Synthesis and in vitro evaluation of novel anti-varicella-zoster virus (VZV) nucleosides.

A series of alkyl-aryl, -phenoxy, and -thiophenoxy bicyclic furo pyrimidine nucleosides have been successfully synthesised by Pd-coupling of 5-iodo-2'-deoxyuridine (IDU) with terminal alkynes, followed by in situ copper-cyclisation. Synthesised compounds (4a-i) showed an anti-VZV activity at low microM concentration, comparable to that of current treatment acyclovir.

Furano pyrimidines as novel potent and selective anti-VZV agents.

Bicyclic furano pyrimidine nucleosides have been found to be highly potent and selective inhibitors of varicella zoster virus (VZV). They are inactive against herpes simplex virus and have been known for several decades as (unwanted) synthetic by-products in the Pd-catalysed coupling of acetylenes to 5-iodo nucleosides. These fluorescent bicyclic nucleosides are now established as a new family of potent antivirals.

Highly potent and selective inhibition of varicella-zoster virus by bicyclic furopyrimidine nucleosides bearing an aryl side chain.

In addition to our recent report on the potent anti-varicella-zoster virus (VZV) activity of some unusual bicyclic furopyrimidine nucleosides bearing long alkyl side chains, we herein report the further significant enhancement of the antiviral potency by inclusion of a phenyl group in the side chain of these compounds. The target structures were prepared by the Pd-catalyzed coupling of a series of para-substituted arylacetylenes with 5-iodo-2'-deoxyuridine, to give intermediate 5-alkynyl nucleosides which were cyclized in the presence of Cu to give the desired bicyclic systems. The compounds display extraordinary potency and selectivity for VZV; the most active are ca.