Herpes simplex virus 1 (HSV-1) is a common human pathogen that causes lifelong latent infection of sensory neurons. Non-nucleoside inhibitors that can limit HSV-1 recurrence are particularly useful in treating immunocompromised individuals or cases of emerging acyclovir-resistant strains of herpesvirus. We report that chebulagic acid (CHLA) and punicalagin (PUG), two hydrolyzable tannins isolated from the dried fruits of Terminalia chebula Retz. (Combretaceae), inhibit HSV-1 entry at noncytotoxic doses in A549 human lung cells. Experiments revealed that both tannins targeted and inactivated HSV-1 viral particles and could prevent binding, penetration, and cell-to-cell spread, as well as secondary infection. The antiviral effect from either of the tannins was not associated with induction of type I interferon-mediated responses, nor was pretreatment of the host cell protective against HSV-1. Their inhibitory activities targeted HSV-1 glycoproteins since both natural compounds were able to block polykaryocyte formation mediated by expression of recombinant viral glycoproteins involved in attachment and membrane fusion. Our results indicated that CHLA and PUG blocked interactions between cell surface glycosaminoglycans and HSV-1 glycoproteins. Furthermore, the antiviral activities from the two tannins were significantly diminished in mutant cell lines unable to produce heparan sulfate and chondroitin sulfate and could be rescued upon reconstitution of heparan sulfate biosynthesis. We suggest that the hydrolyzable tannins CHLA and PUG may be useful as competitors for glycosaminoglycans in the management of HSV-1 infections and that they may help reduce the risk for development of viral drug resistance during therapy with nucleoside analogues.Herpes simplex virus 1 (HSV-1) is an alphaherpesvirus that typically causes mucocutaneous lesions in oral, perioral, and other mucosal sites in the body (58). The virus commonly uses the oropharyngeal mucosa as a port of entry, and after primary infection, establishes a lifelong latent state in the host's trigeminal ganglia sensory neurons. Sporadic recurring infections occur when HSV-1 is reactivated by various stimuli, such as sunlight, immunosuppression, menstruation, fever, or stress (23). Although primary or reactivated HSV-1 infections can be subclinical or manifested by mild and self-limited diseases, severe cases of this viral infection may lead to complications such as keratoconjunctivitis, meningitis, and encephalitis (3, 5). Importantly, corneal HSV-1 infection can lead to stromal keratitis, which remains one of the leading causes of blindness in developing countries (37). More aggressive diseases due to HSV-1 are common in immunocompromised individuals (3,5,23). To date, no treatment has been identified that eradicates or resolves latent infections by this ubiquitous pathogen.HSV-1 viral entry into cells is initiated by interaction of viral envelope glycoproteins (gB and gC) with host cell surface proteoglycans (PGs) conjugated to glycosaminoglycans (GAGs) containing...

The solvent dependences of the populations of the hydroxymethyl rotamers of methyl 2,3,4,6-tetra-O-[2H3]-α-d-glucopyranoside (2a) and methyl 2,3,4-tri-O-[2H3]-α-d-glucopyranoside (6) in 10 and 8 solvents, respectively, have been determined by analysis of 3 J H5,H6R and 3 J H5,H6S values and by consideration of evidence for hydrogen bonding through infrared spectroscopy and 3 J H,OH values. The methods used to determine coupling constants in individual hydroxymethyl rotamers were reexamined, and an improved protocol was developed. When O-6 is methylated (2a), the populations of the hydroxymethyl rotamers are largely independent of solvent polarity at ratios of about 61:38:0 gg:gt:tg, except that a small population (<4%) of the tg rotamer appears in the most polar solvents at the expense of the gg rotamer. When O-6 is unsubstituted (6), there are substantial changes in rotamer population as solvent polarity increases due to loss of intramolecular hydrogen bonding and stabilization of the more polar rotamers. The rotamer populations for 6 return to those adopted by the permethylated derivative (2a) in the most polar solvents. It was concluded that hydrogen bond donation from OH-6 to water is not important in determining hydroxymethyl rotational preferences. The well-known “reversed” chemical shift order of the two C6 protons of peracetylated glucopyranose derivatives was shown to also occur for permethylated derivatives and is ascribed to solvent effects in addition to anisotropy. The solvent effect on the chemical shift difference is attributed to the fact that one of the two protons stays on the same side of the pyranose ring in the two more populated rotamers while the other proton exchanges environments.

Carboxylic acid esters can be prepared in excellent yields at room temperature from an acid and either a phenol or an aliphatic alcohol using the peptide coupling reagents, TBTU, TATU, or COMU, in the presence of organic bases. Reactions using TBTU and TATU are faster but do not occur with tertiary alcohols. Selectivity between reaction with primary or secondary alcohols in diols and polyols can be achieved with choice of base and coupling agent.

This paper is dedicated to Professor Arthur S. Perlin on the occasion of his 67th birthday T. BRUCE GRINDLEY and RASIAH THANGARASA. Can. J. Chem. 68, 1007 (1990). Di-n-butylstannylene acetals of benzyl 4,6-0-benzylidene-a-and -P-D-glucopyranoside and galactopyranoside have been prepared did studied in solution by 'H, I3c, and nuclear magnetic resonance spectroscopy. The species present in solution have been identified from the '19sn nrnr spectral data, by comparison of the l3C nmr chemical shifts of the stannylene acetals and their precursor diols and also by analysis of the products of reactions performed without added nucleophiles. The orientations of the two substituents on the carbons in the pyranose ring attached to the carbons in the stannylene ring determine the structures adopted by the stannylene acetal in solution. If one substituent is axial and the other equatorial, the stannylene acetal exists as a single symmetrical dimer in which the two oxygen atoms in the two 1,3,2-dioxastannolane rings adjacent to the axial substituents are dicoordinate. A stannylene acetal with two adjacent equatorial substituents exists as a non-interconverting mixture of dimers; one with two adjacent axial substituents is present as a rapidly interconverting mixture of dimers, trimers, and tetramers. Benzoylation and benzylation of the latter two types of stannylene acetals have been performed and have been shown to be only slightly regioselective in contrast to the known highly regioselective reactions of the first type. Only when single dimers are present are regiospecific or highly regioselective reactions obtained. The causes of the variation in the species present and of the reaction regioselectivity for different stannylene acetals are discussed.Key words: stannylene acetals, 1,3,2-dioxastannolanes, IL9sn NMR spectroscopy, regioselective reactions, carbohydrates.T. BRUCE GRINDLEY et RASIAH THANGARASA. Can. J. Chem. 68, 1007 (1990). On a prtpart les di-n-butylstannylkne acttals des 4,6-0-benzylidene-a-et -P-glucopyranosides et galactopyranosides de benzyle et on les a ttudits, en solution, en faisant appel h la rtsonance magnttique nucltaire du IH, du 13C et du 119Sn. On a identifit les espkces prtsentes en solution h partir des donntes de la rmn du Il9Sn, par comparaison des dtplacements chimiques en rmn du 13C des stannylkne acttals et des diols qui leur ont donnt naissance ainsi que parune analyse des produits des rtactions rtalistes en l'absence de nucltophiles. Les orientations des deux substituants attachts aux carbones du cycle pyranosique qui font partie du cycle stannylkne dtterminent les structures adopttes par le stannylkne acttal en solution. Si l'un des substituants est axial alors que I'autre est tquatorial, le stannylene acttal existe sous la forme d'un dimkre symttrique unique dans lequel les deux atomes d'oxygkne des deux cycles 1,3,2-dioxastannolanes adjacents aux substituants axiaux sont doublement coordonnts. Un stannylkne acCtal comportant deux substituants tquatoriaux adjacents existe sous la forme...

Polyester dendrimers have been shown to be outstanding candidates for biomedical applications. Compared to traditional polymeric drug vehicles, these biodegradable dendrimers show excellent advantages especially as drug delivery systems because they are non-toxic. Here, advances on polyester dendrimers as smart carriers for drug delivery applications have been surveyed. Both covalent and non-covalent incorporation of drugs are discussed.