The interaction between HIV gp120 and galactose-containing cell surface glycolipids such as GalCer or Gb3 is known to facilitate HIV binding to both CD4+ as well as CD4- cells. In an effort to develop small molecule HIV-1 entry inhibitors with improved solubility and efficacy, we have synthesized a series of C-glycoside analogs of GalCer and tested their anti HIV-1 activity. The analogs were tested for gp120 binding using a HIV-1 (IIIB) V3-loop specific peptide. Two of the six analogs that interfered with gp120 binding also inhibited HIV Env-mediated cell-to-cell fusion and viral entry in the absence of any significant cytotoxicity. Analogs with two side chains did not show inhibition of fusion and/or infection under identical conditions. The inhibition of virus infection seen by these compounds was not coreceptor dependent, as they inhibited CXCR4, CCR5 as well as dual tropic viruses. These compounds showed inhibition of HIV entry at early steps in viral infection since the compounds were inactive if added post viral entry. Temperature-arrested state experiments showed that the compounds act at the level of virus attachment to the cells likely at a pre-CD4 engagement step. These compounds also showed inhibition of VSV glycoprotein-pseudotyped virus. The results presented here show that the glycoside derivatives of GalCer with simple side chains may serve as a novel class of small molecule HIV-1 entry inhibitors that would be active against a number of HIV isolates as well as other enveloped viruses.

A new method for the bromosulfonamidation of olefins using a combination of S, S-dimethyl-N-(p-toluenesulfonyl)sulfilimine and N-bromosuccinimide is disclosed herein.Sulfilimines 1, which have the IUPAC name "sulfimide" remain less explored as synthetic reagents, 1 as compared with the analogous sulfoxides 2, which have found broad use in the area of stereoselective synthesis. 2 There has recently been a resurgence of interest, reflected in the reports regarding the synthesis of enantiomerically enriched sulfilimines 3 and their applications. 4 To the best of our knowledge, in all the chemistry of sulfilimines reported so far, the sulfimide moiety (S=NR) does not participate in the reaction. We disclose herein, a transformation wherein the sulfimide moiety functions as a nucleophile in the N-bromosuccinimide (NBS) promoted, bromosulfonamidation of alkenes.The vicinal halo amine functionality is a structural unit of importance in synthetic organic chemistry. 5 A number of synthetic approaches have been developed to secure this functionality. N,N-Dihalo sulfonamides, 6 N-halo carbamates, 7 N,N-dihalo carbamates, 8 N,N-dibromo phosphoramidate, 9 halo azide, 10 halogen isocyanates, 11 cyanamide/ NBS, 12 sulfonamide/iodonium bis-sym-collidine perchlorate, 13 are the reagents which effect the transformation of alkenes to products with a halo amine moiety. These methods are not without limitations. The reaction of dihalo sulfonamides is not general and straightforward. The products resulting from dihalo sulfonamides and dihalo carbamates have a nitrogen-halogen bond which is to be reduced. The N-halo carbamates require stoichiometric quantities of metal halide as promoters. The dihalo phosphoramidates are not readily available and the halo azides suffer from the drawback of not being easily handled. The utility of the sulfonamide-I + combination has been demonstrated for glycals only. The study of highly regio-and stereoselective amino halogenation of olefins therefore still remains important and challenging.Drawing a parallel with the reactivity of dimethyl sulfoxide with alkenes initiated by NBS, 14 we decided to explore the reaction of alkenes with NBS using S,S-dimethyl-N-(p-toluenesulfonyl)sulfilimine, as the nucleophile (Scheme 1). Scheme 1The results of the study are summarized in Table. S,SDimethyl-N-Ts-sulfilimine was prepared from dimethyl sulfide and Chloramine-T by the Mann-Pope reaction. 15 Dichloromethane and chloroform were found to be the solvents of choice for the reaction. 16 The reaction probably proceeds by an ionic mechanism which would explain the observed regioselectivity; the nucleophilic attack taking place at the carbon atom (anomeric and benzylic) best able to stabilize a partial positive charge. Triacetyl-D-glucal 3, afforded product 4 as the only bromosulfonamide, while related substrate 5, yielded sulfonamides 6 and 7 in a 2: 1 ratio. Dihydropyran afforded isomers 9 and 10. The structures were assigned to the products by comparing their 1 H NMR data with literature values of known (9, 10...

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A combination of experimental J/NOE NMR data with molecular mechanics and dynamics calculations has been used to examine the conformational behaviour and assign the configuration of synthetically prepared epimeric 3-carboxymethyl-O-Gal-(1-->1)-alpha-Man-fluoro-C-glycosides. It is shown that the population distributions around the glycosidic linkages strongly depend on the configuration at the fluorinated carbon of the pseudoacetal residue. It is also shown that these compounds resemble the inhibition ability of sialyl LeX towards P-selectin.

Exact C-glycosides in which the glycosidic oxygen of an O-glycoside is replaced with a methylene group have been advertised as hydrolytically stable mimetics of their parent O-glycosides. While this substitution assures greater stability, the lower polarity and increased conformational flexibility in the intersaccharide linker brought about by this change may compromise biological mimicry. In this regard, C-glycosides in which the pseudoanomeric methylene is replaced with a difluoromethylene group are interesting because the CF 2 group is more of an isopolar replacement for oxygen than a CH 2 . In addition, the CF 2 residue is expected to instill conformational bias into the intersaccharide torsions. Herein is described the synthesis and conformational behavior of the difluoromethylene linked C-glycoside of β-D-galactopyranosyl-(1↔1)-α-D-mannopyranoside. The synthesis centers on the formation of the galactose residue via an oxocarbenium ion-enol ether cyclization. Conformational analysis, using a combination of molecular mechanics, dynamics and NMR spectroscopy. suggests that the difluoro-C-glycoside populates the non-exo-Gal/exo-Man conformer to a major extent (ca 50%), with a minor contribution (∼15%) from the exo-Gal/exo-Man conformer that corresponds to the ground sate of the parent O-glycoside.

[reaction: see text] beta-C-galacto-Pyranosides with CHF and CF2 substitutes for the glycosidic oxygen were prepared through a four-step sequence starting from a central 1-thio-1,2-O-isopropylidene acetal alcohol and different alpha-fluoro- and alpha,alpha-difluoro acids. The key step in the synthesis is the oxocarbenium cyclization of an intermediate enol ether-thioacetal to a C1-substituted glycal.

Bromohydrins have been prepared from beta-methyl-gamma,delta-unsaturated sulfoxides with high regio- and stereoselectivity. The reaction proceeds via neighboring group participation of the sulfinyl moiety with inversion of sulfoxide configuration as proven by an (18)O labeling study and X-ray crystallography.

Dihydroxyalkenes or their monoprotected alcohol derivatives are transformed to 5,5- and 5,6-spiroketals through a sequence involving an initial iodocyclization, followed by a silver triflate mediated spiroketalization step on the derived hydroxy-iodoether.