Bicyclic Nucleoside Inhibitors of Varicella-Zoster Virus: Effect of Terminal Aryl Substitution in the Side-Chain

Abstract

We have previously reported novel, highly potent and selective nucleoside inhibitors of varicella-zoster virus (VZV) bearing unusual fluorescent bicyclic base moieties (McGuigan et al., 1999). These bicyclic furanopyrimidine nucleosides displayed potencies against various strains of VZV in cell culture that were approximately 300-fold higher than those of current anti-VZV agents, such as acyclovir. Our initial studies identified the absolute requirement of a long alkyl side-chain, with an optimal chain length of C8-C10, for antiviral activity (McGuigan et al., 1999) as typified by structures 1a-1c (Figure 1). The key consequence of the obligate long alkyl side-chain is the inherent lipophilicity of the bicyclic systems and we noted that the most active nucleosides had calculated octanol-water logP [ClogP] values in the range of 2.4-3.5 (ClogP version 1.0, Biobyte Corporation, Claremont, CA). With a view to further exploring the structure-activity relationships (SARs) of this class of compounds, we carried out several types of structural modification in the alkyl side-chain. In the first instance, we examined the effect of halogen substitution at the terminus of a nonyl side-chain and found that this was well tolerated; and notably with ClogP values of the ω-halo compounds falling roughly within the previously noted optimal range. We therefore, proposed a possible correlation between antiviral activity and overall compound lipophilicity and also reported on the negative impact on antiviral activity of enhancing the aqueous solubility of the bicyclic nucleosides (Brancale et al., 2000b), this being attributed to the consequential impact on logP. More recently, we sought to constrain the highly flexible alkyl side-chains into more restricted conformations by the use of ring moieties, whilst retaining overall compound lipophilicity. Following the introduction of a phenyl group at the 6-position of the bicyclic base, between the furo ring and the alkyl side-chain, we observed an astonishing enhancement of both potency and selectivity against VZV . The new lead p-alkylphenyl bicyclic nucleosides, as typified by structures 2a-2g (Figure 1), displayed potencies that were, by comparison, approximately 50-fold higher than those for alkyl analogues of identical ClogP. In keeping with our proposed correlation,

When Functionalization Becomes Useful: Ionic Liquids with a “Sweet” Appended Moiety Demonstrate Drastically Reduced Toxicological Effects

“…Probably, the longer the spacer, the higher is the conformational freedom of the cation that hampers the interaction with the cell membrane. This hypothesis is well-supported by the data previously reported in the literature about the increased biological activity of some bicyclic nucleosides with reduced conformational freedom in the side chain. , …”

“…This hypothesis is wellsupported by the data previously reported in the literature about the increased biological activity of some bicyclic nucleosides with reduced conformational freedom in the side chain. 65,66 On the other hand, with the spacer being the same [N 112GAn ] + , the cytotoxicity is also affected by the nature of the alkyl chain, linear or branched. In particular, the linear alkyl chain results in a higher toxicity, as accounted for by the decrease in the IC 50 value from [N 112GA8 ]Br to [N 112GA8L ]Br (Figure 1).…”

Naphthalimide Imidazolium-Based Supramolecular Hydrogels as Bioimaging and Theranostic Soft Materials

“…Probably, in the latter case, the increase in lipophilicity of the chain is counterbalanced by the increase in its conformational freedom, which can make more difficult the interaction with cell membranes. This hypothesis is well supported by previous studies in the literature claiming the increased biological activity of some bicyclic nucleosides with reduced conformational freedom in the side chain. , On the other hand, a similar trend was recently detected, investigating cytotoxic effects of some sugar-based ionic liquids …”

“…This hypothesis is well supported by previous studies in the literature claiming the increased biological activity of some bicyclic nucleosides with reduced conformational freedom in the side chain. 48,49 On the other hand, a similar trend was recently detected, investigating cytotoxic effects of some sugar-based ionic liquids. 24 Interestingly, our results also indicate the pivotal role played by the anion nature.…”