Antonio J. Moreno-Vargas

Glycosidase Inhibitors as Potential HIV Entry Inhibitors

A few alpha-L-fucosidase inhibitors and alpha-D-glucosidase inhibitors have shown in vitro anti-HIV activities, that have been attributed to their ability to inhibit HIV entry. The mechanism of action of inhibitors such as 1-deoxynojirimycin (1) is not clearly established. One possible hypothesis is that the glycosidase inhibition affects the final conformation of the glycoproteins involved in the virus/cell recognition and fusion phenomena. This hypothesis is presented critically and the mechanisms of some glycoprotein biosynthesis are out-lined. Up to now, very few glycosidase inhibitors have been assayed for their potential as HIV entry inhibitors. Further assaying should be done and larger collections of glycosidase inhibitors should be prepared. To help investigations in that perspective, the inhibitory activities of alpha-glucosidase and alpha-L-fucosidase inhibitors have been summarized.

Synthesis of novel pyrrolidine 3,4-diol derivatives as inhibitors of α-L-fucosidases

The stereoselective synthesis of new 3,4-dihydroxypyrrolidine derivatives starting from D-mannose, D-ribose and L-fucose is presented. Two synthetic strategies employing organometallic addition to hemiacetalic sugars followed by selective nucleophilic displacement or conjugate addition of ammonia to conjugate aldonic esters as key steps, are used. The new compounds were assayed for their inhibitory activity towards 13 commercially available glycosidases. Compounds that share the absolute configuration at C(2,3,4,5) of L-fucopyranosides and incorporate aromatic moieties are potent and selective inhibitors of alpha-L-fucosidases in the nM range.

Mixtures of monomeric and dimeric surfactants: hydrophobic chain length and spacer group length effects on non ideality.

Critical micelle concentrations of the Cm TAB+12- s-12 (s=3, 4, 5 and m=10, 12, 14, 16) binary systems have been determined, through conductivity and fluorescence measurements, at 298 K. Application of different theoretical approaches to explain mixed micellization shows that non-ideality of the binary systems follows the trend C16TAB+12-3-12<C14TAB+12-3-12<C12TAB+12-3-12<C10TAB+12-3-12, and C12TAB+12-5-12 approximately C12TAB+12-4-12<C12TAB+12-3-12. Literature data corresponding to the C12TAB+12-2-12, C12TAB+ m-s-m (s=2, 4, 6 and m=12, 14, 16) and TritonX-100+12-s-12 (with s=3, 6, 12) mixtures were considered in order to investigate the hydrophobic chain length and the spacer group length roles on the observed non ideal behavior. It was found that the capacity of the mixture components to form micelles of similar or different shapes plays a major role in non-ideality.

New leads for selective inhibitors of α-l-fucosidases. Synthesis and glycosidase inhibitory activities of [(2R,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]furan derivatives

Readily derived from D-glucose, 5-[(2R,3S,4R)-3,4-dihydroxypyrrolidin-2-yl]-2-methyl-3-furoic esters and amides are selective and competitive inhibitors (K(i)> or = 3 microM) of alpha-L-fucosidase from bovine epididymis and from human placenta.

Synthesis of [(2S,3S,4R)-3,4-Dihydroxypyrrolidin-2-yl]-5-methylfuran-4-carboxylic Acid Derivatives: New Leads as Selective β-Galactosidase Inhibitors

The preparation of [(2S,3S,4R)-3,4-dihydroxypyrrolidin-2-yl]furan derivatives in a stereoselective route starting from D-glucose and ethyl acetoacetate is presented. Ethyl ester (6), N,N-diethylamide (7) and N-isopropylamide (8) have been tested towards 25 glycosidases. Ester (6) is a selective inhibitor of beta-galactosidases. The new compounds represent a new type of imino-C-nucleoside analogues.

Oxidation of polyhydroxyalkyl - heterocycles by cerium (IV). A convenient route to pyrrole-2,5-dicarbaldehydes

Abstract The synthesis of 3-ethoxycarbonyl-2,5-diformylpyrrole ( 2 ) from 3-ethoxycarbonyl-2-methyl-5- d -( arabino -tetritol-1-yl)pyrrole ( 1 ) by oxidation with ceric ammonium nitrate is described. When the reaction was applied to related furan derivatives, ethyl (5 S ,6 R ,7 R )-2-acetyl-5,6,7,8-tetrabenzyloxyoct-2-enoate ( 8 ) was obtained as an E Z mixture.

Allenyl sulfones and allenyl sulfides in the synthesis of 3-pyrrolines. A novel nucleophilic [3 + 2] cycloaddition on allenyl sulfones giving rearranged cycloadducts.

Efficient methodologies for the synthesis of regioisomeric 3-pyrrolines by reaction of electron-deficient imines and sulfur-containing allenyl derivatives are presented. Lithiated thioallenes give 2-aryl-3-phenylsulfonyl-3-pyrrolines, whereas allenyl sulfones furnish the isomeric 2-aryl-4-phenylsulfonyl-3-pyrrolines through migration of the sulfonyl group that catalyzes the nucleophilic [3 + 2] cycloaddition.

Three dimensional structure of a bacterial α-l-fucosidase with a 5-membered iminocyclitol inhibitor

Fucosidases, enzymes that cleave fucose from the non-reducing end of a glycan, represent promising medicinal targets reflecting their roles in cancer metastasis, inflammation, host-parasite interactions and the lysosomal storage disorder fucosidosis. The X-ray crystal structures of Bacteroides thetaiotaomicron GH29 α-l-fucosidase (BtFuc2970) in a new crystal form (at a resolution of 1.59Å) and liganded with a 5-membered iminocyclitol inhibitor (1.73Å) are reported herein. The 5-membered iminocyclitol binds in a (3)E conformation, mimicking the proposed (3)H4 half chair transition-state of the enzyme catalysed reaction, and its Ki for BtFuc2970 was determined as 2μM. Structural analysis of fucosidase inhibition through 5-membered iminocyclitols will aid in the rational design of more potent fucosidase inhibitors for treatment of a range of medical conditions.

Stereoselective synthesis of (2S,3S,4R,5S)-5-methylpyrrolidine-3,4-diol derivatives that are highly selective α-L-fucosidase inhibitors

N-Phenylaminomethyl benzimidazolyl moieties attached at C-2 of (2S,3S,4R,5S)-5-methylpyrrolidine-3,4-diol increase the potency and selectivity of the inhibitory activity of these systems towards alpha-L-fucosidases.

Synthesis and inhibitory activities of novel C-3 substituted azafagomines: a new type of selective inhibitors of α-L-fucosidases.

The synthesis of a novel aminomethyl C-3 substituted L-fuco-azafagomine and of its C-6 epimer from D-lyxose is reported. The key step of the synthesis is the introduction of the biimino (-NH-NH-) moiety by reductive hydrazination of a 1-deoxy-ketohexose with tert-butyl carbazate. The 3-aminomethyl-azafagomine derivatives were used as lead compounds in the generation of libraries of novel types of derivatives by attaching different hydrophobic groups on the aminomethyl substituent through amide linkages. These polyhydroxylated hexahydropyridazines can be viewed as a new type of diaza-C-glycoside analogues having a biimino (-NH-NH-) moiety. The conformational analysis and the glycosidase inhibitory properties of all the new C-3 substituted azafagomines synthesized are also reported. Those having L-fuco configuration have shown a selective inhibition of α-L-fucosidases.