A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound 28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic assays and an EC 50 of 25nM in the...
The synthesis and biochemical evaluation of novel cyanothiazolidine inhibitors of dipeptidyl peptidase 4 (DPP4) is described. Their main structural feature is a constrained bicyclic core that prevents the intramolecular formation of inactive cyclic species. The inhibitors show good to moderate biochemical potency against DPP4 and display distinct selectivity profiles towards DPP7, DPP8 and DPP9 depending...
The synthesis and biochemical characterization of AX4697, a fluorescent, bisindolylmaleimide-derived probe for PKCα and β, is described. AX4697 was able to quantify changes in PKC expression in drug-treated Jurkat cells and was shown to covalently label PKCα on C619, a residue that sits just outside the active site.
An efficient synthesis of the title compounds as pure enantiomers is reported. The method is based on the intramolecular trapping of a carbocation generated by acid treatment of exo-Co 2 (CO) 6 -propargyl alcohols by a stereochemically controlled secondary hydroxy group located in a suitable chain.
Enantioselective direct Michael additions of ketones using (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine as a catalyst are described. Michael adducts with up to 91% e.e. were obtained by the reaction of alkylidene malonates with simple unactivated ketones under mild reaction conditions.
The trapping under different conditions of the carbocation generated by acid treatment of chiral Co 2 (CO) 6 -complexed propargylic secondary alcohols permitted access to either diastereoisomer at the propargylic center. Further chemical manipulations provided either enantiomer of enantiomerically pure 1,2-difunctionalized molecules such as 1,2-diols, α-hydroxy-aldehydes or α-hydroxy-acids.
A two step procedure for the synthesis of chiral tetradentate sulfonamide ligands is reported. The ligands are easily prepared from the corresponding bissulfonamide complexes by directed metallation followed by quenching with either ketones or carbon dioxide in 47 to 82 % yield. Preliminary results indicate that these complexes are efficient catalysts in the asymmetric addition of alkyl groups to...
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