Serendipitous discovery of light-induced (<Emphasis Type="Italic">In Situ</Emphasis>) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor

Background

Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results.

Results

Studies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC₅₀ of 36 μM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC₅₀ of 2.1 μM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5.

Conclusion

We report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common mechanism of inhibitory action for these scaffolds.

     

Pyrohydrolytic separation technique for fluoride and chloride from radioactive liquid wastes

A rapid method for simultaneous determination of fluorine and chlorine in radioactive liquid wastes with ion chromatography after pyrohydrolysis separation was proposed for routine analysis. The elements were separated from radioactive liquid wastes by pyrohydrolysis and were subsequently determined with ion chromatograpy. Total time taken to determine these elements is about 45 min including 30 min for the pyrohydrolysis and 15 min for ion chromatography. The results of recovery tests ranged 95% or above. The limits of detection for F and Cl are 0.5 and 0.8 mg kg⁻¹, respectively.     

Bounded mean oscillation and bandlimited interpolation in the presence of noise

We study some problems related to the effect of bounded, additive sample noise in the bandlimited interpolation given by the Whittaker-Shannon-Kotelnikov (WSK) sampling formula. We establish a generalized form of the WSK series that allows us to consider the bandlimited interpolation of any bounded sequence at the zeros of a sine-type function. The main result of the paper is that if the samples in this series consist of independent, uniformly distributed random variables, then the resulting bandlimited interpolation almost surely has a bounded global average. In this context, we also explore the related notion of a bandlimited function with bounded mean oscillation. We prove some properties of such functions, and in particular, we show that they are either bounded or have unbounded samples at any positive sampling rate. We also discuss a few concrete examples of functions that demonstrate these properties.     

Twisting (conformational changes)-based selective 2D chalcogeno podand fluorescent probes for Cr(III) and Fe(II)

The fluorenoazomethine containing chalcogeno podand fluorescent probes having N, O/S/Se coordinating donor unit show donor specific 'turn-on' recognition property towards metals (Cr(III), Fe(II) and Cu(II)), where the fluorescence signals are controlled by the conformational change of the ligand framework on binding with the metal ion.     

Nature and strength of C-H···O interactions involving formyl hydrogen atoms: computational and experimental studies of small aldehydes

Structural and electronic properties of C-H···O contacts in compounds containing a formyl group are investigated from the perspective of both hydrogen bonding and dipole-dipole interactions, in a systematic and graded approach. The effects of α-substitution and self-association on the nature of the formyl H-atom are studied with the NBO and AIM methodologies. The relative dipole-dipole contributions in formyl C-H···O interactions are obtained for aldehyde dimers. The stabilities and energies of aldehyde clusters (dimer through octamer) have been examined computationally. Such studies have an implication in crystallization mechanisms. Experimental X-ray crystal structures of formaldehyde, acrolein and N-methylformamide have been determined in order to ascertain the role of C-H···O interactions in the crystal packing of formyl compounds.     

渐近正则映射对的不动点

本文在P一致凸Banach空间中证明了浙近正则映射对的若干不动点定理．在Hilbert空间，Lp空间，Hardy空间Hp和Sobolev空间Hp，k中，1＜P＜＋∞，k≥0，也建立了这些映射的若干不动点定理．本文推广了Gornicki[9，10]，Kruppel[11,12]和其他作者的结果。     

Photo-transformations of 6-chloro-3-propargyloxy-2-aryl-4-oxo-4H-1-benzopyran: 1,4-hydrogen abstraction in propargylethers

1,4-Biradicals generated in the Norrish type-II reactions of 3-propargyloxy-2-arylchromones lead to cyclic products involving the 2-aryl group. The formation and distribution of products varied with the nature of 2-aryl group.     

An oxidimetric method for the determination of thiophanatemethyl in commercial formulations

A simple, accurate and reliable titrimetric method is described for the determination of thiophanate-methyl, an important commercial fungicide. The method is based on its direct titration at room temperature with ammonium hexanitratocerate(IV) in sulphuric acid medium in the presence of potassium iodate as catalyst. The method permits detection of the end-point visually, potentiometrically or spectrophotometrically. The proposed method is recommended for routine determination of the fungicide in its commercial formulations.     

Error analysis for convex separable programs: Bounds on optimal and dual optimal solutions

Computable lower and upper bounds on the optimal and dual optimal solutions of a nonlinear, convex separable program are obtained from its piecewise linear approximation. They provide traditional error and sensitivity measures and are shown to be attainable for some problems. In addition, the bounds on the solution can be used to develop an efficient solution approach for such programs, and the dual bounds enable us to determine a subdivision interval which insures the objective function accuracy of a prespecified level. A generalization of the bounds to certain separable, but nonconvex, programs is given and some numerical examples are included.