Chloromethyl Glycosides as Versatile Synthons to Prepare Glycosyloxymethyl-Prodrugs.

This work investigates the addition of monosaccharides to marketed drugs to improve their pharmacokinetic properties for oral absorption. To this end, a set of chloromethyl glycoside synthons were developed to prepare a variety of glycosyloxymethyl-prodrugs derived from 5-fluorouracil, thioguanine, propofol and losartan. Drug release was studied in vitro using β-glucosidase confirming rapid conversion of the monosaccharide prodrugs to release the parent drug, formaldehyde and the monosaccharide.

A comprehensive overview of substrate specificity of glycoside hydrolases and transporters in the small intestine : "A gut feeling".

The human body is able to process and transport a complex variety of carbohydrates, unlocking their nutritional value as energy source or as important building block. The endogenous glycosyl hydrolases (glycosidases) and glycosyl transporter proteins located in the enterocytes of the small intestine play a crucial role in this process and digest and/or transport nutritional sugars based on their structural features. It is for these reasons that glycosidases and glycosyl transporters are interesting therapeutic targets to combat sugar related diseases (such as diabetes) or to improve drug delivery.

Synthesis and cellular uptake of carbamoylated mannose derivatives.

A series of 3-carbamoyl- and 2,3-dicarbamoyl-mannose derivatives were synthesized, conjugated to a fluorescent dye (Cy5, AF 647 or NBD) and their cellular uptake in A549 and THP-1 cell lines was studied by FACS. In contrast to earlier studies on carbamoyl mannosides, the observed uptake was not related to carbamoyl group on the mannose residue but rather to the cyanine dye attached, a trend previously observed for Cy5-fructose conjugates. The NBD-conjugates however, showed a temperature and concentration dependent uptake in case of mannose conjugates.

Non-steroidal steroid receptor modulators.

The discovery and launch of non-steroidal ligands for estrogen receptors (ERs) and for androgen receptors (ARs) demonstrated the potential of these ligands as therapeutic agents. Based on these successes, substantial attention in the past ten years has been focused on identifying non-steroidal ligands for all of the classic steroid receptors. Non-steroidal ligands are currently in the discovery phase or in early clinical development for glucocorticoid, mineralocorticoid and progesterone receptors, and therefore must still provide evidence of their beneficial features over their steroidal counterparts.

Non-steroidal subtype selective estrogens.

The biological effects of estrogens are thought to be mediated by two receptors referred to as ERalpha and ERbeta. In recent years significant efforts have been devoted to the design of subtype selective ligands. These ligands are valuable tools to establish the precise biological role of each of the subtypes and to develop new generations of therapeutics.

Identification of "latent hits" in compound screening collections.

The relatively low hit rates found from high-throughput screening have raised a question on whether this technology alone is sufficient to maximally exploit the full potential of current corporate screening collections. The present study introduces a knowledge-based strategy for identifying "latent hits", i.e.