Bader A. Salameh

1H-1,2,3-Triazol-1-yl thiodigalactoside derivatives as high affinity galectin-3 inhibitors

Galactose C3-triazole derivatives were synthesized by Cu(I)-catalyzed cycloaddition between acetylenes and galactose C3-azido derivatives. Evaluation against galectin-3, 7, 8N (N-terminal) and 9N (N-terminal) revealed 1,4-disubstituted triazoles to be high-affinity inhibitors of galectin-3 with selectivity over galectin-7, 8N, and 9N. Conformational analysis of 1,4-di- and 1,4,5-tri-substituted galactose C3-triazoles suggested that a triazole C5-substituent interfered sterically with the galectin proteins, which explained their poor affinities compared to the corresponding 1,4-disubstituted triazoles. Introduction of two 1,4-disubstituted triazole moieties onto thiodigalactoside resulted in affinities down to 29 nM for galectin-3.

Scalable Synthesis of L-Iduronic Acid Derivatives via Stereocontrolled Cyanohydrin Reaction for Synthesis of Heparin-Related Disaccharides

L-ido cyanohydrin 3 was prepared from diacetone-D-glucose in four steps and 76% overall yield and 90% de via cyanohydrin reaction of aldehyde 2. This process can be scaled to provide >1 mol of pure L-ido cyanohydrin 3. Cyanohydrin 3 was elaborated to 1,2-isopropylidine-protected L-ido nitrile (8), iduronic amide 9, and known carboxy ester 10. Coupling of 8 and 9 with glucosamine donors leads to new types (6-cyano and 6-carboxamide) of heparin-related disaccharides.

Fragment-based development of triazole-substituted O-galactosyl aldoximes with fragment-induced affinity and selectivity for galectin-3

A fragment-based development of 3C-triazol-1-yl-O-galactopyranosyl aldoximes led to the discovery of highly selective and high affinity (K(d) down to 11 microm) small monosaccharide based inhibitors of galectin-3. Galectin-7, 8 N-terminal CRD, and 9 N-terminal CRD bound the inhibitors only weakly. The galectin-3 selectivity was hypothesized to stem from interaction of the aldoxime moiety with a site not present in the other galectins.

Isothiocyanato derivatives of sugars in the stereoselective synthesis of spironucleosides and spiro-C-glycosides

Abstract A stereocontrolled synthesis of pyranoid and furanoid spironucleosides and spiro- C -glycosides ( d - ribo and d - arabino configurations) of oxazolidines, oxazolines and perhydrooxazines via isothiocyanato sugar derivatives is reported. The intermediate isothiocyanates are prepared from sugar spiroketals by stereoselective opening of the acetal ring with trimethylsilyl N - and C -nucleophiles, and later formation of the isothiocyanato group.

Galectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition.

Discovery of glycan‐competitive galectin‐3‐binding compounds that attenuate lung fibrosis in a murine model and that block intracellular galectin‐3 accumulation at damaged vesicles, hence revealing galectin‐3–glycan interactions involved in fibrosis progression and in intracellular galectin‐3 activities, is reported. 3,3′‐Bis‐(4‐aryltriazol‐1‐yl)thiodigalactosides were synthesized and evaluated as antagonists of galectin‐1, ‐2, ‐3, and ‐4 N‐terminal, ‐4 C‐terminal, ‐7 and ‐8 N‐terminal, ‐9 N‐terminal, and ‐9 C‐terminal domains. Compounds displaying low‐nanomolar affinities for galectins‐1 and ‐3 were identified in a competitive fluorescence anisotropy assay. X‐ray structural analysis of selected compounds in complex with galectin‐3, together with galectin‐3 mutant binding experiments, revealed that both the aryltriazolyl moieties and fluoro substituents on the compounds are involved in key interactions responsible for exceptional affinities towards galectin‐3. The most potent galectin‐3 antagonist was demonstrated to act in an assay monitoring galectin‐3 accumulation upon amitriptyline‐induced vesicle damage, visualizing a biochemically/medically relevant intracellular lectin–carbohydrate binding event and that it can be blocked by a small molecule. The same antagonist administered intratracheally attenuated bleomycin‐induced pulmonary fibrosis in a mouse model with a dose/response profile comparing favorably with that of oral administration of the marketed antifibrotic compound pirfenidone.

Isothiocyanatoulosonates, a new type of glycosyl isothiocyanate useful for the stereocontrolled synthesis of thiohydantoin spironucleosides

Abstract Thiohydantoin spironucleosides and N -alkyl, aryl and glycosyl derivatives are prepared in a stereocontrolled manner, by reaction of ammonia, and of alkyl-, aryl- and glycosyl-amines with a new class of isothiocyanato sugar: the methyl 2-deoxy-2-isothiocyanatohex-2-ulofura(pyra)nosonates. The reaction produces an intermediate thioureido derivative, which spontaneously cyclates to give the spironucleoside in high yield. Alternatively, the same spironucleosides are prepared from methyl 2-amino-2-deoxy-hex-2-ulofura(pyra)nosonates and alkyl-, aryl- and glycosyl isothiocyanates. Some of the prepared compounds have the structure of N -nucleoside of spirothiohydantoins.

Chiral thioxohydroimidazoles with two sugar moieties. N-, C-, and spiro-nucleosides

Abstract 2-Amino (alkyl and arylamino)-2-deoxy- d -fructose and different sugar isothiocyanates are used in the diastereoselective synthesis of chiral imidazolidine-2-thione N -nucleosides 12 – 23 . Water β-elimination of these compounds produces imidazoline-2-thione N -nucleosides 27 – 31 , whereas cyclodehydration of the same products gives, with high stereoselectivity, chiral spironucleosides with an N -glycosyl radical 34 – 37 . Conformational aspects of some of the prepared compounds are discussed.

Synthesis of some new carbohydrate-containing thiouriedonaphtho-quinones

New alkyl, aryl, and glycosylthiouriedo derivatives of 2,3-diamino-1,4-naphthoquinone were synthesized via the reaction of isothiocyanates with 2,3-diamino-1,4-naphthoquinone. The new compounds were fully characterized through their physicochemical properties.

A concise route to 4-aminomethylpyrazoles and 4-aminomethylisoxazoles from acetylacetone-derived hexahydropyrimidines under mild conditions

Acetylacetone was successfully used as a precursor of 4-aminomethylpyrazoles and 4-aminomethylisoxazoles in a two step process at ambient temperature. In the first step, acetylacetone was transformed to the corresponding hexahydropyrimidines (1,3-diazinanes) via two consecutive one-pot Mannich aminomethylations. Hexahydropyrimidines were then treated with hydrazine, phenylhydrazine, and hydroxylamine, respectively, to obtain the corresponding 4-aminomethylpyrazoles and 4-aminomethylisoxazoles in good yields. The hexahydropyrimidine ring decomposed providing the title compounds and a reasonable mechanism has been proposed.

Synthesis and characterization of new N-phenylmaleimide thioglycosides

Thioglycosides derivatives of N-phenylmaleimide have been prepared by the reaction of derivatives of 1-thio-d-glucopyranose, d-galactopyranose, d-lactose, and d-maltose with 3,4-dichloro-N-phenylmaleimide. The reaction of 3,4-dichloro-N-phenyl maleimide with sugar thiols (protected or unprotected) took place by displacement of both chlorine atoms by sulfide nucleophile giving the corresponding bis-thioglycoside products.