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A divergent and regioselective synthesis of 1,2,4- and 1,2,5-trisubstituted imidazoles from a readily available (two steps) common intermediate has been developed. This methodology is based on the regiocontrolled N-alkylation of 1-(N,N-dimethylsulfamoyl)-5-iodo-2-phenylthio-1H-imidazole (10). When this intermediate is engaged in reaction with methyl triflate, selective formation of the corresponding 1,2,5-trisubsituted 1H-imidazole is observed. NMR studies have revealed that this regioselectivity can be accounted for by in situ rapid isomerization of 10 into its 1,2,4-isomer (13) followed by regiospecific N-alkylation of the latter. Conversely, when key intermediate 10 is slowly added to Meerwein's salt, isomerization can be constrained and regiospecific N-alkylation of 10 leads to 1,2,4-trisubstituted 1H-imidazole with a high selectivity. The general character of this methodology has been illustrated by showing that iodine in position 4 or 5 could be easily substituted by an aryl group by Suzuki coupling, whereas the phenylthio group at position 2 could, after oxidation into sulfone, be displaced by nucleophilic substitution.

Galectins form a family of carbohydrate-binding proteins defined by their affinity for beta-galactosides containing glycoconjugates. The carbohydrate recognition domain (CRD) is responsible for the specificity of galectins for saccharides. This binding may result in modulated cell proliferation, cell death and cell migration, three processes that are intimately involved in cancer initiation and progression. Galectins can also display protein-protein types of interactions with their binding partners. Certain galectins directly involved in cancer progression seem to be promising targets for the development of novel therapeutic strategies to combat cancer. Indeed, migrating cancer cells resistant to apoptosis still constitute the principal target for the cytotoxic drugs used to treat cancer patients. Reducing the levels of migration in apoptosis-resistant cancer cells can restore certain levels of sensitivity to apoptosis (and so to pro-apoptotic drugs) in restricted-migration cancer cells. Anti-galectin agents can restrict the levels of migration of several types of cancer cell and should therefore be used in association with cytotoxic drugs to combat metastatic cancer. We provide experimental proof in support of this concept. While the present review focuses on various experimental strategies to impair cancer progression by targeting certain types of galectins, it pays particular attention to glioblastomas, which constitute the ultimate level of malignancy in primary brain tumors. Glioblastomas form the most common type of malignant brain tumor in children and adults, and no glioblastoma patient has been cured to date., Journal Article, Research Support, Non-U.S. Gov't, Review, info:eu-repo/semantics/published

Various mono- and disaccharides were grafted onto a steroid backbone. Whereas in vitro these glycosylated steroids had no cytotoxic effects on six different human cancer cell lines, several of the glycosylated steroids under study did significantly modify the levels of in vitro migration of the human U373 glioblastoma, the A549 non-small-cell-lung cancer (NSCLC), and the PC-3 prostate cancer cells, with more pronounced effects in the case of a monosubstituted beta-L-fucopyranosyl-steroid (19), a monosubstituted beta-D-isomaltosyl-steroid (22), and a monosubstituted beta-D-lactosyl-steroid (24). These three compounds significantly increased the survival of conventional mice grafted subcutaneously with the P388 lymphoma, a lymphoma that metastasizes toward the liver. In vivo, the monosubstituted beta-D-lactosyl-steroid (24) also increased the antitumor effectiveness of cisplatin, a cytotoxic pro-apoptotic drug, in the case of the P388 lymphoma model. This compound also increased the survival of immunodeficient mice into whose brains human U373 glioblastoma cells had been orthotopically grafted., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

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Disubstituted-alpha-chloroenamines are useful synthetic intermediates which bad earlier been prepared by the reaction of tertiary amides with phosgene. The toxicity of the latter led us to systematically investigate new synthetic routes towards alpha-chloro- and alpha-bromoenamines. The reactions of various halogenating agents (SOCl2, diphosgene, triphosgene, OPCl3, OPBr3) with tertiary amides followed by the addition of triethylamine have been studied. Thionyl chloride was found unsuitable for the preparation of alpha-chloroenamines. Of the other halogenating agents, OPCl3 and OPBr3 were found the most practical. The generality of the method is illustrated by the synthesis of fifteen alpha-chloroenamines and six alpha-bromoenamines. (C) 1998 Elsevier Science Ltd. All rights reserved.

Doctorat en sciences chimiques -- UCL, 1994

The configuration of the two isomers obtained by the Diels-Alder reaction of the 2-azadiene 1 with N-phenylmaleimide II (scheme) is established by X-ray diffraction: The cycloaddition takes place with a high endo selectivity. The geometry of the two isomers is similar and the piperidone ring has a twist conformation in both molecules

Trimethylsilyl triflate and t-butyldimethylsilyl triflate can be used as activating reagents in the cycloaddition between chiral oxazoline 1 and cyclopentadiene. However, better results were obtained with a mixture of trifluoroacetic anhydride and trimethylsilyl triflate which gave rise to highly stereoselective cycloaddition. Oxazoline 1 and siloxy-2-azadienes 7, 8, 9 and 10 afforded, in the presence of trimethylsilyl triflate, cycloadducts 11, 12, 13 and 14. Endo adducts were obtained with open chain dienes, whereas exo adducts were the major products with the cyclic diene 10. The diastereoselectivity was highly dependent upon the structure of the diene.

The structures of the two title compouds have been established by X-ray diffraction analysis The configurations of the products obtained show that the Diels-Alder reaction of the azadiene I and II with vinylsulfones (scheme) occurs with full exo selectivity.