We report, for the first time, that certain N-acetylthiourea derivatives serve as highly potent and isozyme selective activators for the recombinant form of human histone deacetylase-8 in the assay system containing Fluor-de-Lys as a fluorescent substrate. The experimental data reveals that such activating feature is manifested via decrease in the Km value of the enzyme’s substrate and increase in the catalytic turnover rate of the enzyme

Histone Deacetylases (HDACs) are intimately involved in the epigenetic regulation, and thus are one of the key therapeutic targets for cancer, and two HDAC inhibitors, namely suberoylanilide hydroxamic acid (SAHA) and romidepsin have been recently approved for the cancer treatment. Since the screening and detailed characterization of HDAC inhibitors has been time consuming, we synthesized Coumarin-SAHA (c-SAHA) as a fluorescent probe for determining the binding affinities (K d ) and the dissociation off-rates (k off ) of the enzyme-inhibitor complexes. The determination of the above parameters relies on the changes in the fluorescence emission intensity (λ ex = 325 nm, λ em = 400 nm) of c-SAHA due to its competitive binding against other HDAC inhibitors, and such determination neither requires employment of polarization accessories nor is dependent on the fluorescence energy transfer from the enzyme's tryptophan residues to the probe. Our highly sensitive and robust analytical protocol presented herein is applicable to most of the HDAC isozymes, and it can be easily adopted in a high-throughput mode for screening the HDAC inhibitors as well as for quantitatively determining their K d and k off values.

Organocatalysis has developed rapidly in recent years. [1] Among the catalysts developed for this purpose, proline derivatives have risen to prominence, and have been used to catalyze a wide range of reactions.[2] While covalent bonds are used to connect the stereocontrolling moiety and the pyrrolidine backbone in most of these derivatives, Clarke and Fuentes recently reported the first example of modularly designed prolinamide-based catalysts that self-assemble under the reaction conditions through hydrogen-bonding interactions.[3] Although the reported method only affords mediocre enantioselectivities in most cases, the advantage of this approach is obvious: Modification of the catalyst structure only needs simple replacement of the modules, while further chemical synthesis is avoided. Moreover, a library of diverse organocatalysts may be more efficiently obtained for catalyst screening and structure modification. [4] During our recent study of quinine derivative-catalyzed enantioselective reactions, [5,6] we envisioned that ionic interactions may be utilized for the self-assembly of modularly designed organocatalysts. Our hypothesis is shown in Equation (1) with proline as the reaction-center module. When proline and a tertiary amine carrying a thiourea moiety (the stereocontrolling module) [7] are mixed, an acid-base reaction between the carboxylic acid and the tertiary amine groups should lead to an ammonium salt.[8] Ionic interactions between the ammonium and the carboxylate should cause these two modules to self-assemble, [9] forming a potential organocatalyst incorporating both the proline reaction center and a stereocontrolling moiety. Michael addition is one of the most important CÀC bondforming reactions in organic synthesis, [10] and many proline derivatives [11] have been developed as catalysts for the direct addition of ketones/aldehydes to nitroalkenes since the proline-catalyzed direct nitro-Michael addition was discovered.[12] To test our hypothesis, the nitro-Michael addition reaction was adopted as a model. Herein we wish to report our preliminary results of using these self-assembled organocatalysts in the direct Michael addition of ketones and aldehydes to nitroalkenes.Acetone and trans-b-nitrostyrene were selected as the model substrates in the preliminary screening. Acetone is one of the most problematic substrates for the nitro-Michael addition. To our knowledge, enantiomeric excesses of over 90 % have been obtained for the Michael product with an acetone substrate in only two cases [11i-j] , despite the fact that numerous sophisticated proline derivatives have been reported as the organocatalysts for this reaction.[11p-q] Readily available a-amino acids, such as proline, glycine, alanine, ltert-leucine, and phenylglycine, [13] were selected as the reaction-center modules, whereas some readily accessible cinchona alkaloid derivatives were chosen as the stereocontrolling modules (Scheme 1). Some typical results [13] are summarized in Table 1.The enantiomers of proline show strong matching ...

Diphenyl diselenides and disulfides undergo facile cleavages by indium(I) iodide and the corresponding generated selenate and thiolate anions condense in situ with alkyl or acyl halides present in the reaction mixture. Thus, a simple, efficient, and general procedure has been developed for the synthesis of unsymmetrical diorganyl selenides, sulfides (thioethers), selenoesters, and thioesters by this one-pot reaction at room temperature.

We present a purely numerical approach in Cartesian grid, for efficient computation of Hartree-Fock (HF) exchange contribution in the HF and density functional theory models. This takes inspiration from a recently developed algorithm [Liu et al., J. Chem. Theor. Comput. 13, 2571]. A key component is the accurate evaluation of electrostatic potential integral, which is the rate-determining step. This introduces the Fourier convolution theorem in conjunction with a range-separated Coulomb interaction kernel. The latter is efficiently mapped into real grid through a simple optimization procedure, giving rise to a constraint in the range-separated parameter.The overall process offers logarithmic scaling with respect to molecular size. It is then extended towards global hybrid functionals such as B3LYP, PBE0 and BHLYP within pseudopotential Kohn-Sham theory, through an LCAO-MO ansatz in Cartesian grid, developed earlier in our laboratory. For sake of comparison, a parallel semi-numerical approach has also been worked out that exploits the familiar Obara-Saika recursion algorithm. An excellent agreement between these two routes is demonstrated through total energy and orbital energy in a series of atoms and molecules (including 10 πelectron molecules), employing an LANL2DZ-type basis function. A critical analysis of these two algorithms reveals that the proposed numerical scheme could lead to very attractive and competitive scaling. The success of our approach also enables us for further development of optimally tuned range-separated hybrid and hyper functionals.