Effect of substituents on the polarographic behaviour of α-arylhydrazononitriles: Further evidence for the mechanism of polarographic reduction of α-arylhydrazononitriles

The polarographic behaviour of the α-arylhydrazonomesoxalonitrile derivatives (IIb-i) and of 2-arylhydrazono-3-keto-3-phenylpropionitriles (IIIb-f) was investigated. With the exception of the nitro-substituted derivatives IIh, i and IIIf all the investigated compounds showed polarographic waves similar to that of their respective parent compounds IIa and IIIa. The m-nitro derivatives IIh and IIIf were firstly reduced in a 4 e wave to the corresponding hydroxylamino derivatives which were subsequently reduced in the manner common to other α-arylhydrazononitriles. On the other hand, the p-nitro derivative IIi was first reduced to the hydroxylamino derivative which then lost water to yield the corresponding quinoneimine. Reduction of the latter product in a 2 e wave gave the p-amino derivative IIe, which then underwent 4 e reduction to p-phenylenediamine and aminomalonitrile. The E_1/2 values corresponding to reduction of the arylhydrazonic moiety of compounds IIa-i and IIIa-f at different pH values were correlated to Hammett's different sigma sets. Analysis of the results provided evidence for the suggested mechanism for reduction of these compounds.     

A novel approach for characterizing protein ligand complexes: molecular basis for specificity of small-molecule Bcl-2 inhibitors

The increasing diversity of small molecule libraries has been an important source for the development of new drugs and, more recently, for unraveling the mechanisms of cellular events-a process termed chemical genetics.(1) Unfortunately, the majority of currently available compounds are mechanism-based enzyme inhibitors, whereas most of cellular activity regulation proceeds on the level of protein-protein interactions. Hence, the development of small molecule inhibitors of protein-protein interactions is important. When screening compound libraries, low-micromolar inhibitors of protein interactions can be routinely found. The enhancement of affinities and rationalization of the binding mechanism require structural information about the protein-ligand complexes. Crystallization of low-affinity complexes is difficult, and their NMR analysis suffers from exchange broadening, which limits the number of obtainable intermolecular constraints. Here we present a novel method of ligand validation and optimization, which is based on the combination of structural and computational approaches. We successfully used this method to analyze the basis for structure-activity relationships of previously selected (2) small molecule inhibitors of the antiapoptotic protein Bcl-xL and identified new members of this inhibitor family.     

A Mössbauer investigation of zirconium distribution and diffusion in ball milled nanocrystalline iron powders

Ball milled nanocrystalline iron with minor zirconium additions was examined using ⁵⁷Fe Mössbauer spectroscopy and X-ray diffraction. Powder samples were synthesized using 0, 5, and 10 wt.% zirconium additions and milled at room temperature for periods up to 24 h. Progressive decrease in grain size as determined by X-ray diffraction was observed as a function of milling time. Mössbauer spectroscopy indicates increased iron-zirconium coordination with increased milling time. After milling, the powder samples were then heat treated in an inert atmosphere of argon at up to 925 K for various times up to 25 min. Analysis of X-ray peak line width (FWHM) was used to characterize grain size and grain growth kinetics as a function of heat treatment, milling time, and alloy content and reveal an increasingly finer post-heated structure in the alloy samples containing more zirconium. Mössbauer measurements were made and suggest Zr is steadily distributed into the Fe lattice with milling and rapidly diffuses to the grain boundaries with heat treatment. The impurity-rich grain boundaries appear to considerably stabilize the refined structure.     

Reactions with heterocyclic amidines 1. Cyanoethylation of cyclic amidines

2-Amino-5-phenyl-1,3,4-oxadiazole ( 1a ) and 2-amino-1,3,4-thiadiazole ( 1b ) reacted with acrylonitrile to yield β-cyanoethylamino derivatives. On the other hand, 2-amino-4-phenylthiazole ( 2 ) reacted with acrylonitrile under the same experimental conditions to yield a di-β-cyanoethylaminothiazole derivative. 3-Phenyl-Δ²-1,2,4-triazoline-5-thione reacted with acrylonitrile to yield the corresponding adduct. The structure of the adduct was established by its conversion into the acid 13 which could be synthesised via another independent route.     

On right G-semilocal rings

The notion of semilocal ring is extended to the classes of right G-semilocal and right N-semilocal rings. We explore the algebraic properties of such classes and study their relations with many other rings such as clean, exchange and I-finite rings. Localization of right G-semilocal rings is considered.     

Reactions with cyclic amidines II. The behaviour of cyclic amidines toward ethoxycarbonyl and aroyl isothiocyanates

The behaviour of the aminopyrazole derivatives 1a-c, 2-amino-4-phenylthiazole (2) and 2-amino-5-phenyl-1,3,4-thiadiazole (3) toward the action of ethoxycarbonyl and benzoyl iso-thiocyanate is reported. The data clearly demonstrates the dependence of the nature of the products obtained from the reaction of isothiocyanates with cyclic amidines on the nature of the substituents on the heterocyclic ring.     

Design and synthesis of some new tri-substituted pyrazole derivatives as anticancer agents

A new series of tri-substituted pyrazole derivatives were designed as anti-cancer agents and synthesized, starting with the formylation of semicarbazone via the Vilsmeier–Haack reaction to give 3-(4-bromophenyl)-1H-pyrazole-4-carbaldehyde I which was the precursor of compounds 1–9. The new chemical entities were screened for their anti-cancer activity on various human cancer cell lines, namely: hepatocellular carcinoma HepG2, breast cancer MCF-7, lung carcinoma A549 and prostatic cancer PC3. Most of the synthesized compounds showed remarkable activity on the tested cell lines, while compound 2 had the highest potency against the HepG2 cell line with an IC₅₀ of 9.13 µM compared with doxorubicin (IC₅₀ = 34.24 µM), the reference standard used in this study, and compound 7 was the most active on the rest of the three cell lines; MCF-7, A549 and PC3 (IC₅₀ = 16.52, 6.52 and 9.13 µM, respectively) relative to IC₅₀ = 20.85, 5.93 and 38.02 µM of the standard. Thus, some of the synthesized tri-substituted pyrazole derivatives, specially 2 and 7, have the potential to be developed into potent anticancer agents.     

Peak effect studies in single crystals CeRu2 and 2H-NbS2

We have studied the peak effect (PE) phenomenon in single crystals of weakly pinned superconductors CeRu₂ and 2H-NbS₂. 2H-NbS₂ is iso-structural and iso-electronic to 2H-NbSe₂, whose similarity with CeRu₂ as regards the PE representing the order-to-disorder transformation of the flux line lattice was claimed some time ago. We report on the step change in equilibrium magnetization across the peak effect in CeRu₂. We also present the vortex phase diagram of 2H-NbS₂ obtained from the magnetization data, and compare the PE phenomenon in 2H-NbS₂ and 2H-NbSe₂.