Partner und Internationale Organisationen
(Englisch)
|
A, B, HR, CZ, DK, F, D, GR, H, IRL, I, LV, NL, N, PL, P, SK, SI, E, S, CH, GB
|
Abstract
(Englisch)
|
Inhibitors of a-mannosidases are potential anti-cancer agents. Inhibitors of a-glucosidases and a-L-fucosidases are potential anti-HIV entry inhibitors. Known glycosidase inhibitors such as azasugars have failed in the chemical trials because of their toxicity, more specific and less toxic inhibitors must be found. This implies the invention of new structures that can be potent and specific glycosidase inhibitors and also allow for a large molecular diversity by combinatorial techniques. Collaboration with prof.Robina in Seville has produced a variety of new leads (4 publications in 2002). New (1®2)-c, (1®3)-c and homo(1®3)-C-linked imino-disaccharides starting from levoglucosenone and isolevoglucosenone have been made for the first time. The synthesis of [(2s,3s,4r)-3,4-dihydroxy-pyrrolidin-2-yl]-5-methylfuran-4-carboxylic acid derivatives have been made and found to be new leads as selective b-galactosidase inhibitors. An efficient combinatorial method for the discovery of glycosidase inhibitors has been proposed. Dynamic imine library formed in solution provides a fast route to drug discovery. Imine formation from (2r,3r,4s)-2-aminomethyl-3,4-dihydroxypyrrolidine and sublibrary of aldehydes can be used for the efficient discovery of glycosidase (a-mannosidase thus far) inhibitors through a new combinatorial approach. when the equilibrium amine + aldehydes = imines is reached under dilute conditions, a mixture of imines is produced and can be screened by the glycosidase, which binds preferentially to the best inhibitor. In collaboration with professor Pierre Sinaÿ (ENS, Paris, 1 publication), seven- and eight-membered carbasugar analogs were made and their inhibitory activities determined toward glycosidases. The group has exchanged information in the topics of glycochemistry , glycobiology and organic synthesis. Exchange of synthetic techniques, starting materials and synthetic intermediates. Dr. Kren's group supplied the group with glycosidases, Vogel's group has run enzymatic inhibition assays for all the partners. The WG is active in the synthesis of monosaccharide and disaccharide mimetics and analogs. It develops efficient synthesis of compounds that are potential anti-bacterial, anti-viral and anti-cancer agents. Priority is given to molecular diversity and to speed of the bioassays. Exchange of graduate students and of chemicals has allowed to increase the efficiency of discovery applying combinatorial methods, including dynamic libraries exposed to glycosidases. New leads as glycosidase inhibitors have been discovered and some of them are new leads as anti-cancer agents. The groups of I. Robina (Seville) and P. Vogel (Lausanne) have been integrated in the European FP6 TRIoH (Targeting Replication and Integration of.HIV) and will pursue the efforts carried out during the COST D13/0001/99 research program. A great number of C-linked disaccharides, some of them analogues of sugar epitopes responsible for the human anti-cancer inmune response (Thomsen-Friedenreich epitope), others new leads as human fucosyltransferase inhibitors have been prepared. Imino-C-linked disaccharide have also been prepared and evaluated for their inhibitory activities toward 25 glycosidases. Simultaneously, analogues of natural products such as swainsonine, lentiginosine, castanospermine and casuarine, as well as new polyhydroxypyrrolidine and piperidine have been made and evaluated for their glycosidase inhibitory activities. Polyhydroxycyclopentylamines have also revealed interesting inhibitory activities. Each laboratory of the WG has brought its own approaches, its own specialties that have merged finally into powerful methodologies. These efforts have been reported in publications in refereed scientific journals and reviews.
|
