Synthesis and structure-activity relationship of 4-(1,3-benzothiazol-2-yl)-thiophene-2-sulfonamides as cyclin-dependent kinase 5 (cdk5)/p25 inhibitors.

4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately potent inhibitor of cyclin-dependent kinase 5 (cdk5) from a HTS screen. The synthesis and SAR around this hit is described. The X-ray coordinates of ligand 4a with cdk5 are also reported, showing an unusual binding mode to the hinge region via a water molecule.

Synthesis and evaluation of 2-pyridylbenzothiazole, 2-pyridylbenzoxazole and 2-pyridylbenzofuran derivatives as 11C-PET imaging agents for beta-amyloid plaques.

The syntheses and SAR of new series of beta-amyloid binding agents are reported. The effort to optimize signal-to-background ratios for these ligands are described. Compounds 8, 21 and 30 displayed desirable lipophilicity and pharmacokinetic properties. Compounds 8 and 21 were evaluated with in vitro autoradiographic studies and in vivo in APP/PS1 transgenic mice. It is shown that it was possible to increase the signal-to-background ratios compared to PIB 1, as demonstrated by compounds 8 and 21.

Identification of non-muscle myosin heavy chain as a substrate for Cdk5 and tool for drug screening.

BACKGROUND: Deregulated activation of cyclin-dependent kinase-5 (Cdk5) is implicated in neurodegenerative disorders such as Alzheimer's disease. One of the restricting factors for developing specific Cdk5 inhibitors is the lack of reproducible and well-characterized cellular in vitro assay systems. METHODS: HEK293 cells were transfected with Cdk5 and its activator p25 as a starting point for an assay to screen for Cdk5 kinase inhibitors. To identify suitable substrates for Cdk5 we utilized an antibody that recognizes phospho serine in a consensus motif for Cdk substrates. RESULTS: Western blot analysis of transfected cells detected a 200 kDa band that was identified, by mass spectrometry, as non-muscle myosin heavy chain, type B (NMHC-B). Phosphorylation of NMHC-B was evident only in cells that were double transfected with Cdk5/p25 and was dose-dependently inhibited by Roscovitine and other Cdk5 inhibitors. Cdk5 was found to phosphorylate NMHC-B also in the human neuroblastoma SH-SY5Y cell line. CONCLUSION: A novel Cdk5 substrate NMHC-B was identified in this study. A cellular assay for screening of Cdk5 inhibitors was established using NMHC-B phosphorylation as a read-out in Cdk5/p25 transfected HEK293 cells. A novel Cdk5 inhibitor was also pharmacologically characterized in this assay system.

Author Correction: Cytotoxic unsaturated electrophilic compounds commonly target the ubiquitin proteasome system.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cytotoxic unsaturated electrophilic compounds commonly target the ubiquitin proteasome system.

A large number of natural products have been advocated as anticancer agents. Many of these compounds contain functional groups characterized by chemical reactivity. It is not clear whether distinct mechanisms of action can be attributed to such compounds. We used a chemical library screening approach to demonstrate that a substantial fraction (~20%) of cytotoxic synthetic compounds containing Michael acceptor groups inhibit proteasome substrate processing and induce a cellular response characteristic of proteasome inhibition. Biochemical and structural analyses showed binding to and inhibition of proteasome-associated cysteine deubiquitinases, in particular ubiquitin specific peptidase 14 (USP14). The results suggested that compounds bind to a crevice close to the USP14 active site with modest affinity, followed by covalent binding. A subset of compounds was identified where cell death induction was closely associated with proteasome inhibition and that showed significant antineoplastic activity in a zebrafish embryo model. These findings suggest that proteasome inhibition is a relatively common mode of action by cytotoxic compounds containing Michael acceptor groups and help to explain previous reports on the antineoplastic effects of natural products containing such functional groups.

Toward Novel Antioxidants: Preparation of Dihydrotellurophenes and Selenophenes by Alkyltelluride-Mediated Tandem S(RN)1/S(H)i Reactions(1).

Reaction of 1-(2-iodophenyl)-1-methyloxirane (12) with 2 equiv of sodium n-butyltellurolate (n-BuTeNa), generated by the sodium borohydride reduction of di-n-butyl ditelluride, in THF, affords 2,3-dihydro-3-hydroxy-3-methylbenzo[b]tellurophene (13) in 62% yield, together with a small quantity of 1-(n-butyltelluro)-2-phenyl-2-propanol (27). This transformation presumably involves a tandem S(RN)1/S(H)i sequence. Similar reactions of 1-(benzylseleno)-2-phenyl-2-propanol (5a, R = Me) and 1-allyloxy-2-iodobenzene (15) afforded 2,3-dihydro-3-hydroxy-3-methylbenzo[b]selenophene (17, 74%), and 3-(n-butyltelluro)methyl-2,3-dihydrobenzo[b]furan (18, 50%), respectively. Lithium alkyltellurolates, generated by direct tellurium insertion into the required alkyllithium, or sec-butyl or tert-butyl substitution on tellurium provide product distributions similar to those observed for reactions involving n-BuTeNa. Lithium or sodium phenyltellurolate returned only starting materials from these reaction mixtures. The 2-[2-(n-butyltelluro)-1-hydroxy-1-methyl]ethylphenyl radical (14) is estimated to cyclize with k(c) = 5 x 10(8) s(-)(1) at 25 degrees C. The tandem S(RN)1/S(H)i sequence has been applied to the preparation of the antioxidant analogues, 5-hydroxy-2,3-dihydrobenzo[b]tellurophene and selenophene (31, 32).

Core refinement toward permeable ß-secretase (BACE-1) inhibitors with low hERG activity.

By use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of these compounds are reported, together with physicochemical properties and structure-activity relationships based on in vitro data. Four crystal structures of diverse amidines binding in the active site are deposited and discussed. Inhibitors of BACE-1 with 3 µM to 32 nM potencies in cells are shown, together with data on in vivo brain exposure levels for four compounds. The results presented show the importance of the core structure for the profile of the final compounds.

Strong valence-band offset bowing of ZnO1-xSx enhances p-type nitrogen doping of ZnO-like alloys.

Photoelectron spectroscopy, optical characterization, and density functional calculations of ZnO1-xSx reveal that the valence-band (VB) offset E(v)(x) increases strongly for small S content, whereas the conduction-band edge E(c)(x) increases only weakly. This is explained as the formation of local ZnS-like bonds in the ZnO host, which mainly affects the VB edge and thereby narrows the energy gap: E(g)(x=0.28) approximately E(g)(ZnO)-0.6 eV. The low-energy absorption tail is a direct Gamma(v)-->Gamma(c) transition from ZnS-like VB. The VB bowing can be utilized to enhance p-type N(O) doping with lower formation energy DeltaH(f) and shallower acceptor state in the ZnO-like alloys.

Structure-activity relationship of thiopyrimidines as mGluR5 antagonists.

Structure-activity relationship investigations of the thiopyrimidine (1), an HTS hit with micromolar activity as a metabotropic glutamate receptor 5 (mGluR5) antagonist, led to compounds with sub-micromolar activity.

Design and synthesis of 6-anilinoindazoles as selective inhibitors of c-Jun N-terminal kinase-3.

The structure-based design and synthesis of a new series of c-Jun N-terminal kinase-3 inhibitors with selectivity against JNK1 and p38alpha is reported. The novel series of substituted 6-anilinoindazoles were designed based on a combination of hits from high throughput screening and X-ray crystal structure information of the compounds crystallized into the JNK3 ATP binding active site.