39 research outputs found
Титульні сторінки та зміст
Kidney injury triggers fibrosis, the final common pathway of chronic kidney disease (CKD). The increase of CKD prevalence worldwide urgently calls for new therapies. Available systemic treatment such as rapamycin are associated with serious side effects. To study the potential of local antifibrotic therapy, we administered rapamycin-loaded microspheres under the kidney capsule of ureter-obstructed rats and assessed the local antifibrotic effects and systemic side effects of rapamycin. After 7 days, microsphere depots were easily identifiable under the kidney capsule. Both systemic and local rapamycin treatment reduced intrarenal mTOR activity, myofibroblast accumulation, expression of fibrotic genes, and T-lymphocyte infiltration. Upon local treatment, inhibition of mTOR activity and reduction of myofibroblast accumulation were limited to the immediate vicinity of the subcapsular pocket, while reduction of T-cell infiltration was widespread. In contrast to systemically administered rapamycin, local treatment did not induce off target effects such as weight loss. Thus subcapsular delivery of rapamycin-loaded microspheres successfully inhibited local fibrotic response in UUO with less systemic effects. Therapeutic effect of released rapamycin was most prominent in close vicinity to the implanted microspheres. (C) 2014 Elsevier Ltd. All rights reserved
Combining two-directional synthesis and tandem reactions: desymmetrisation by intramolecular cycloaddition/triazoline fragmentation
Synthesis of spiro quasi[1]catenanes and quasi[1]rotaxanes via a templated backfolding strategy
Due to their well-defined three-dimensional geometry, spiro compounds are widely utilized in drug research. From the central tetrahedral carbon atom, besides the regular structure, an inverted spiro connectivity may be envisioned. Here we disclose the synthesis of this molecule class that we have coined quasi[1]catenanes. Next to their fascinating and aesthetic shape, the higher compactness as compared to regular spiro bicycles is noteworthy. To enable synthetic access to compact entangled multimacrocyclic molecules, we have developed a new strategy. The key element is a template, which is covalently connected to the linear precursors, and spatially directs the sterically congested backfolding macrocyclizations that are required to give quasi[1]catenanes. Similarly, quasi[1]rotaxanes are made
PegPhos: a monodentate phosphoramidite ligand for enantioselective rhodium-catalysed hydrogenation in water
A BICOL derived monodentate phosphoramidite ligand gives ee’s up to 89% in the enantioselective Rh-catalysed hydrogenation of N-acyl dehydroalanine using water as the solvent.
Synthesis of Constrained Tetracyclic Peptides by Consecutive CEPS, CLIPS, and Oxime Ligation
In Nature, multicyclic
peptides constitute a versatile molecule
class with various biological functions. For their pharmaceutical
exploitation, chemical methodologies that enable selective consecutive
macrocyclizations are required. We disclose a combination of enzymatic
macrocyclization, CLIPS alkylation, and oxime ligation to prepare
tetracyclic peptides. Five new small molecular scaffolds and differently
sized model peptides featuring noncanonical amino acids were synthesized.
Enzymatic macrocyclization, followed by one-pot scaffold-assisted
cyclizations, yielded 21 tetracyclic peptides in a facile and robust
manner
Carbosilane Dendrimeric Carbodiimides: Site Isolation as a Lactamization Tool
The convergent syntheses of three generations of carbosilane dendrimeric carbodiimides are described. The wedge-type building blocks were synthesized in a divergent way, starting from allyl chloride and a repetitive sequence of hydrosilylation with HSiCl3 and a Grignard reaction with allylmagnesium bromide. Hydrogenation of the terminal double bonds led to inert and stable wedges. The chloride substitutent at the focal point was transformed into several functional groups that eventually led to dendrimeric structures with a carbodiimide core. The extent of the site isolation effect of the dendrimers was studied with dilution experiments monitored by FT-IR spectroscopy on the corresponding dendrimeric ureas. These studies showed that only the first generation self-aggregates via hydrogen bonding, while the second and the third do not, implying isolation of core-bound moieties. The dendrimeric carbodiimides mediated lactamization reactions to obtain homodiketopiperazines.
A Short Covalent Synthesis of an All-Carbon-Ring [2]Rotaxane
While
the current supramolecular syntheses of [2]rotaxanes are
generally efficient, the final product always retains the functional
groups required for non-covalent preorganization. A short and high-yielding
covalent-template-assisted approach is reported for the synthesis
of a [2]rotaxane. A terephthalic acid template core preorganizes the
covalently connected ring precursor fragments to induce a clipping-type
cyclization over the thread moiety. Cleavage of the temporary ester
bonds that connect the ring and thread fragments liberates the [2]rotaxane
A One-Pot "Triple-C" Multicyclization Methodology for the Synthesis of Highly Constrained Isomerically Pure Tetracyclic Peptides
Synthesis of Water-Soluble Scaffolds for Peptide Cyclization, Labeling, and Ligation
The synthesis and applications of water-soluble scaffolds that conformationally constrain side chain unprotected linear peptides containing two cysteines are described. These scaffolds contain a functionality with orthogonal reactivity to be used for labeling and ligation. This is illustrated by the chemical ligation of two dissimilar constrained peptides via oxime ligation or strain-promoted azide–alkyne cycloaddition in aqueous media