ChemInform Abstract: An Efficient Combinatorial Method for the Discovery of Glycosidase Inhibitors.

Abstract

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Novel 2-[(benzylamino)methyl]pyrrolidine-3,4-diol derivatives as α-mannosidase inhibitors and with antitumor activities against hematological and solid malignancies

“…Probably, due to the pharmacophoric properties and the lipophilic character of the biphenyl moiety compound 30 proved to be more active toward the cancer cells tested than the simpler analogues 29, 31, 32-34 and those described earlier. [28][29][30] Our data show that the new functionalized pyrrolidines affect the expression of genes involved in cell cycle progression thereby arresting cells in the G2/M phase of cell cycle and causing the upregulation of cell cycle inhibitors CDKN1A and CDKN1C, as well as the downregulation of CDC25A cyclin E1, and of MYBL2 which, conversely, promote cells cycle progression. These experiments establish the new a-mannosidase inhibitors as effective cell cycle modulators.…”

“…24,25 In order to facilitate the discovery of new specific a-mannosidase inhibitors, we have developed a new synthesis protocol leading to the generation of a new family of compounds with selective and competitive inhibitory activity for a-mannosidase from jack bean. [26][27][28] The novel a-mannosidase inhibitors contain in their chemical structure a pyrrolidine ring functionalized to allow their internalization by cells. The introduction of a lipophilic ester moiety led to derivatives that inhibit the growth of human cancer cells lines more efficiently than swainsonine and the other analogues.…”

Synthesis of Novel 3-Amino(Hydroxy)methyl-l-fuco-Azafagomines as Leads for Selective Inhibitors of α-l-Fucosidases

“…They can be considered as the first examples of aza-C-glycosides having a biimino (-NH-NH-) moiety and constitute interesting lead compounds for the search of new a-L-fucosidase inhibitors. In spite of that compound 3b is a weak inhibitor of a-L-fucosidases, its triamino functionality makes it a promising candidate for the discovery of fucosidase inhibitors by combinatorial procedures through the approach of dynamic libraries of imines 20 or through the in situ evaluation of libraries of amides. 7 The use of lead compounds 3a and 3b in the synthesis of new derivatives, the conformational analysis and the corresponding biological studies are currently in progress in our laboratory and will be reported in due course.…”

Discovery of potent inhibitors of human β-tryptase from pre-equilibrated dynamic combinatorial libraries

“… 3 Besides its application in supramolecular chemistry and metal complex formation, 4 DCC has also been applied successfully for the identification of ligands and inhibitors for enzymes and other biomolecules. 5 , 6 For example, Otto and Sanders have employed disulfide exchange for a series of structurally diverse dithiol building blocks to generate diverse DCLs of the corresponding macrocycles for the identification of receptors for different supramolecular guests. 4a , b Using hydrazone-based DCLs, Sanders et al have identified linear receptors for dihydrogen phosphate ions 4 c and macrocyclic receptors for heavy metal ions.…”

“…4 d Although a powerful and promising concept, DCC nevertheless still has its limitations, as not every reaction is compatible with the physiological conditions dictated by a bio-molecular target. So far, disulfide 5 and imine exchanges 6 have been used successfully for DCC in biological systems. As imines are inherently unstable in aqueous media, they are often reduced to amines after the amplification process prior to analysis in order to prevent screening and isolation problems.…”