Virtually all chronic kidney diseases progress towards tubulointerstitial fibrosis. In vitro, Y-box protein-1 (YB-1) acts as a central regulator of gene transcription and translation of several fibrosis-related genes. However, it remains to be determined whether its pro- or antifibrotic propensities prevail in disease. Therefore, we investigated the outcome of mice with half-maximal YB-1 expression in a model of renal fibrosis induced by unilateral ureteral obstruction. Yb1 animals displayed markedly reduced tubular injury, immune cell infiltration and renal fibrosis following ureteral obstruction. The increase in renal YB-1 was limited to a YB-1 variant nonphosphorylated at serine 102 but phosphorylated at tyrosine 99. During ureteral obstruction, YB-1 localized to the cytoplasm, directly stabilizing Col1a1 mRNA, thus promoting fibrosis. Conversely, the therapeutic forced nuclear compartmentalization of phosphorylated YB-1 by the small molecule HSc025 mediated repression of the Col1a1 promoter and attenuated fibrosis following ureteral obstruction. Blunting of these effects in Yb1 mice confirmed involvement of YB-1. HSc025 even reduced tubulointerstitial damage when applied at later time points during maximum renal damage. Thus, phosphorylation and subcellular localization of YB-1 determines its effect on renal fibrosis in vivo. Hence, induced nuclear YB-1 shuttling may be a novel antifibrotic treatment strategy in renal diseases with the potential of damage reversal.

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The direct pyrrolidine-catalyzed a-sulfenylation of aldehydes and ketones with the commercially available, very cheap chemical tetramethylthiuram disulfide (thiram) is described. The dithiocarbamoyl derivatives are obtained in good to excellent yields (47-98%). In the case of a-substituted aldehydes the protocol allows the generation of quaternary stereocenters. The sensibility of the a-sulfenylated carbonyl compounds for racemization has been investigated.

Abstract:The enantioselective organocatalytic nucleophilic addition of thiols to isatin-derived ketimines has been developed utilizing only 1 mol% of an enantiopure BINOL-derived phosphoric acid.The new protocol provides a series of isatin-derived N,S-acetals in high yields (up to 98%) and high enantioselectivities (up to 93% ee).

The first enantio- and chemoselective Brønsted-acid catalysed reduction of α-keto esters with catecholborane has been developed. The α-hydroxy esters were obtained under mild reaction conditions in virtually quantitative yields and excellent enantioselectivities. With slight modifications both enantiomers can be obtained without any loss of selectivity.