Cationic iridium complexes with chiral P,Nligands and tetrakis [3,5-(trifluoromethyl)phenyl]borate (BAr F ) as the counterion are efficient homogeneous catalysts for the enantioselective hydrogenation of olefins. The complexes are readily prepared, air-stable, and easy to handle. In contrast to chiral rhodium-and ruthenium-phosphine catalysts, they do not require the presence of a polar coordinating group near the C C bond. In the hydrogenation of unfunctionalized arylolefins, high enantioselectivities of > 95% ee with turnover numbers of up to 5000 and turnover frequencies of > 5000 h À1 have been achieved.

SUMMARY To elucidate how the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor alirocumab modulates lipoprotein(a) [Lp(a)] plasma levels, the authors performed a series of Lp(a) uptake studies in primary human hepatocytes and dermal fibroblasts and measured Lp(a) secretion from human hepatocytes. They found that Lp(a) cellular uptake occurred in a low-density lipoprotein receptor–independent manner. Neither PCSK9 nor alirocumab altered Lp(a) internalization. By contrast, the secretion of apolipoprotein (a) from human hepatocytes was sharply increased by PCSK9, an effect that was reversed by alirocumab. They propose that PCSK9 does not significantly modulate Lp(a) catabolism, but rather enhances the secretion of Lp(a) from liver cells.

Phosphinooxazolines 1 (phox ligands) have been successfully applied in many different enantioselective metal-catalyzed processes. [1] We have recently found that iridium ± phox complexes are efficient catalysts for the enantioselective hydrogenation of unfunctionalized alkenes, [2] a class of substrates that gives unsatisfactory results with other catalysts. [3] The best enantioselectivities (up to 99 % ee) have been observed for 1-alkyl-1,2-diaryl-substituted alkenes, while other alkenes such as monoaryl-1,2-dimethyl-substituted alkenes are converted with only moderate enantiomeric excesses. Here we report a new class of ligands, the phosphinite ± oxazolines 2, which induce high enantioselectivity with a much broader range of alkenes and, thus, significantly enhance the scope of Ir-catalyzed hydrogenation.Both enantiomers of the phosphinite ± oxazoline ligands 2 are readily prepared in three to four steps, starting from imidates 5 or carboxylic acids 8 and l-serine methyl ester hydrochloride (4) or the corresponding d isomer (Scheme 1). Special precautions had to be taken in the peptide coupling Scheme 1. Synthesis of compounds 2 for which R 3 Ph. a) 4,

Our studies confirm that cabazitaxel is more active in ABCB1(+) cell models due to its reduced affinity for P-gp compared to docetaxel.

Both enantiomers are readily prepared of phosphinite–oxazoline ligands 1 from the D and L enantiomers of serine (see Scheme). Iridium complexes derived from these ligands (the structure of one complex is shown) are excellent catalysts for the enantioselective hydrogenation of unfunctionalized alkenes. R1=ferrocenyl, aryl; R2=alkyl, benzyl.

Since 2012, clinical trials dedicated to proprotein convertase subtilisin kexin type 9 (PCSK9) inhibition with monoclonal antibodies (mAbs) have unambiguously demonstrated robust reductions not only in low-density lipoprotein (LDL) cholesterol (LDL-C) but also in lipoprotein (a) [Lp(a)] levels. The scientific literature published prior to those studies did not provide any evidence for a link between PCSK9 and Lp(a) metabolism. More recent investigations, either in vitro or in vivo, have attempted to unravel the mechanism(s) by which PCSK9 mAbs reduce circulating Lp(a) levels, with some showing a specific implication of the LDL receptor (LDLR) in Lp(a) clearance whereas others found no significant role for the LDLR in that process. This elusive pathway appears clearly distinct from that of the widely prescribed statins that also enhance LDLR function but do not lower circulating Lp (a) levels in humans. So how does PCSK9 inhibition with mAbs reduce Lp(a)? This still remains to be established.

The incorporation of carbon-14 allows tracking of organic molecules and provides vital knowledge on their fate. This information is critical in pharmaceutical development, crop science and human food safety evaluation. Herein, a transition-metal-catalyzed procedure enabling carbon isotope exchange on aromatic nitriles is described. Utilizing the radiolabeled precursor Zn([ 14 C]CN) 2 , this protocol allows the insertion of the desired carbon tag without need of structural modifications, in a single step. Reducing synthetic costs and limiting the generation of radioactive waste, this procedure will facilitate the labeling of nitrile containing drugs and accelerate 14 C-based ADME studies supporting drug development. File list (2) download file view on ChemRxiv Manuscript.pdf (1.47 MiB) download file view on ChemRxiv Supporting Information.pdf (9.86 MiB)

No abstract