Polycations are promising vectors for the delivery of siRNA therapeutics but they often suffer from toxicity and low in vivo delivery efficacy. This study tests the hypothesis that combining fluorination and bioreducibility of polycations will overcome problems with both the toxicity and delivery efficacy. To test the hypothesis, we synthesized bioreducible (RHB) and nonreducible (NHB) poly(amido amine)s. The RHB were additionally fluorinated using reaction with heptafluorobutyric anhydride to obtain F-RHB. We found that both RHB and F-RHB showed significantly reduced cytotoxicity compared with NHB, which allowed their safe use in a wider range of doses than NHB. All three synthesized polycations formed polyplexes with siRNA. F-RHB achieved the best siRNA silencing efficacy in multiple cell lines in vitro, which was at least in part because of fluorination-induced enhancement of cellular uptake and improved endosomal escape. Lastly, F-RHB showed greatly improved Luc silencing efficacy in tumors in vivo when compared with polyplexes based on RHB, NHB, as well as control poly(ethylenimine) (PEI). This study suggests that combining fluorination with bioreducibility of polycations is a promising strategy to the design of siRNA delivery vectors with improved toxicity and in vivo activity profiles.
Chiral carboxylic acids are important compounds because of their prevalence in pharmaceuticals,n atural products and agrochemicals.A symmetric hydrogenation of a,bunsaturated carboxylic acids has been widely recognized as one of the most efficient synthetic approaches to afford such compounds.Although related asymmetric hydrogenation of diand trisubstituted unsaturated acids with noble metals is well established, asymmetric hydrogenation of challenging tetrasubstituted a,b-unsaturated carboxylic acids is rarely reported. We demonstrate enantioselective hydrogenation of cyclic and acyclic tetrasubstituted a,b-unsaturated carboxylic acids via cobalt(II) catalysis.T his protocol showed broad substrate scope and gave chiral carboxylic acids in good yields with excellent enantiocontrol (up to 98 %y ield and 99 %e e). Combined experimental and computational mechanistic studies support aCo II catalytic cycle involving migratory insertion and s-bond metathesis processes.DFT calculations reveal that enantioselectivity may originate from the steric effect between the phenyl groups of the ligand and the substrate.
[reaction: see text] In DMSO cleavage of triethylsilyl (TES) ethers by o-iodoxybenzoic acid (IBX) was significantly faster than cleavage of tert-butyldimethylsilyl (TBS) ethers or further oxidation into carbonyl compounds. In most cases, TES protecting groups could be removed in good to excellent yields within 1 h, whereas similar TBS protecting groups remained intact under the same conditions. The procedure also could be adapted for direct one-pot conversion of TES ethers into carbonyl compounds.
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