Chemical synthesis and immunosuppressive activity of dipalmitoyl phosphatidylinositol hexamannoside.

Phosphatidylinositol mannosides (PIMs) isolated from mycobacteria have been identified as an important class of phosphoglycolipids with significant immune-modulating properties. We present here the synthesis of dipalmitoyl phosphatidylinositol hexamannoside (PIM(6)) 1 and the first reported functional biology of a synthetic PIM(6). Key steps in the synthetic protocol included the selective glycosylation of an inositol 2,6-diol with a suitably protected mannosyl donor and construction of the glycan core utilizing a [3 + 4] thio-glycosylation strategy. The target 1 was purified by reverse phase chromatography and characterized by standard spectroscopic methods, HPLC, and chemical modification by deacylation to dPIM(6). The (1)H NMR spectrum of synthetic dPIM(6) obtained from 1 matched that of dPIM(6) obtained from nature. PIM(6) (1) exhibited dendritic cell-dependent suppression of CD8(+) T cell expansion in a human mixed lymphocyte reaction consistent with the well established immunosuppressive activity of whole mycobacteria.

Inhibition of cobalamin-dependent methionine synthase by substituted benzo-fused heterocycles.

The cobalamin-dependent cytosolic enzyme, methionine synthase (EC.2.1.1.13), catalyzes the remethylation of homocysteine to methionine using 5-methyltetrahydrofolate as the methyl donor. The products of this remethylation--methionine and tetrahydrofolate--participate in the active methionine and folate pathways. Impaired methionine synthase activity has been implicated in the pathogenesis of anaemias, cancer and neurological disorders. Although the need for potent and specific inhibitors of methionine synthase has been recognized, there is a lack of such agents. In this study, we designed, synthesized and evaluated the inhibitory activity of a series of substituted benzimidazoles and small benzothiadiazoles. Kinetic analysis revealed that the benzimidazoles act as competitive inhibitors of the rat liver methionine synthase, whilst the most active benzothiadiazole (IC(50) = 80 microm) exhibited characteristics of uncompetitive inhibition. A model of the methyltetrahydrofolate-binding site of the rat liver methionine synthase was constructed; docking experiments were designed to elucidate, in greater detail, the binding mode and reveal structural requirements for the design of inhibitors of methionine synthase. Our results indicate that the potency of the tested compounds is related to a planar region of the inhibitor that can be positioned in the centre of the active site, the presence of a nitro functional group and two or three probable hydrogen-bonding interactions.

Highly (E)-selective Wadsworth-Emmons reactions promoted by methylmagnesium bromide.

An experimentally simple protocol for the very highly (E)-selective Wadsworth-Emmons reaction [(E):(Z) selectivities in excess of 180:1 in some cases] of a range of straight-chain and branched aliphatic, substituted aromatic, and base-sensitive aldehydes via reaction with an alkyl diethylphosphonoacetate and MeMgBr is reported.

Asymmetric synthesis of 3,4-anti- and 3,4-syn-substituted aminopyrrolidines via lithium amide conjugate addition.

The diastereoselective conjugate addition of homochiral lithium amides to methyl 4-(N-allyl-N-benzylamino)but-2-enoate has been used as the key step in a simple and efficient protocol for the preparation of 3,4-substituted aminopyrrolidines. This protocol provides a complementary and stereoselective route to both anti- and syn-3-amino-4-alkylpyrrolidines as well as anti- and syn-3-hydroxy-4-aminopyrrolidines, in high de and ee viabeta-amino enolate functionalisation. This methodology has been applied to the synthesis of anti-(3S,4S)- and syn-(3R,4S)-3-methoxy-4-(N-methylamino)pyrrolidine.

An improved method for Lewis acid catalyzed phosphoryl transfer with Ti(t-BuO)4.

Several inorganic esters have been evaluated as phosphoryl transfer catalysts. Of these, Ti(t-BuO)(4) was found to be the most effective catalyst giving excellent yields of the desired phosphate esters. The loading of the catalyst could be reduced to a little as 5 mol % for a majority of substrates with no loss in the yield of product. This methodology is significantly more versatile than using TiCl(4) and is suitable for the phosphorylation of more complex carbohydrates and molecules of biological interest.