The development of a biotechnological platform for the removal of waste products (e.g. uremic toxins), often bound to proteins in plasma, is a prerequisite to improve current treatment modalities for patients suffering from end stage renal disease (ESRD). Here, we present a newly designed bioengineered renal tubule capable of active uremic toxin secretion through the concerted action of essential renal transporters, viz. organic anion transporter-1 (OAT1), breast cancer resistance protein (BCRP) and multidrug resistance protein-4 (MRP4). Three-dimensional cell monolayer formation of human conditionally immortalized proximal tubule epithelial cells (ciPTEC) on biofunctionalized hollow fibers with maintained barrier function was demonstrated. Using a tailor made flow system, the secretory clearance of human serum albumin-bound uremic toxins, indoxyl sulfate and kynurenic acid, as well as albumin reabsorption across the renal tubule was confirmed. These functional bioengineered renal tubules are promising entities in renal replacement therapies and regenerative medicine, as well as in drug development programs.
Glycosyl cations are crucial intermediates formed during enzymatic and chemical glycosylation. The intrinsic high reactivity and short lifetime of these reaction intermediates make them very challenging to characterize using spectroscopic techniques. Herein, we report the use of collision induced dissociation tandem mass spectrometry to generate glycosyl cations in the gas phase followed by infrared ion spectroscopy using the FELIX infrared free electron laser. The experimentally observed IR spectra were compared to DFT calculated spectra enabling the detailed structural elucidation of elusive glycosyl oxocarbenium and dioxolenium ions.
Uronic acids are important constituents of polysaccharides found on the cell membranes of different organisms. To prepare uronic‐acid‐containing oligosaccharides, uronic acid 6,3‐lactones can be employed as they display a fixed conformation and a unique reactivity and stereoselectivity. Herein, we report a highly β‐selective and efficient mannosyl donor based on C‐4 acetyl mannuronic acid 6,3‐lactone donors. The mechanism of glycosylation is established using a combination of techniques, including infrared ion spectroscopy combined with quantum‐chemical calculations and variable‐temperature nuclear magnetic resonance (VT NMR) spectroscopy. The role of these intermediates in glycosylation is assayed by varying the activation protocol and acceptor nucleophilicity. The observed trends are analogous to the well‐studied 4,6‐benzylidene glycosides and may be used to guide the development of next‐generation stereoselective glycosyl donors.
The stereoselective synthesis of glycosidic bonds is the main challenge of oligosaccharide synthesis. Neighboring-group participation (NGP) of C2 acyl substituents can be used to provide 1,2-trans-glycosides. Recently, the application of NGP has been extended to the preparation of 1,2-cis-glycosides with the advent of C2 chiral auxiliaries. However, this methodology has been strictly limited to the synthesis of 1,2-cis-gluco-type sugars. Reported herein is the design and synthesis of novel mannosyl donors which provide 1,2-cis-mannosides by NGP of thioether auxiliaries. A key element in the design is the use of (1) C4 locked mannuronic acid lactones to enable NGP of the C2 auxiliary. In addition to C2 participation a new mode of remote participation of the C4 benzyl group was identified and provides 1,2-cis-mannosides.
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