Isosteres of Natural Phosphates. Methylene and Hydroxyrnethylene Analogues of Tyrosine O-Phosphate

Abstract

The ability of phosphonic acid analogues isosteric with natural phosphate esters to Serve as inhibitors of enzymatic phosphate hydrolysis has been documented in a wide variety of systems.¹ The use of such an analogue in place of the natural phosphate ester provides a functionality which the enzyme may not be able to distinguish from the natural ester, but which is incapable of being hydrolyzed. In some instances the use of hydroxymethylene analogues has resulted in a greater degree of recognition, and resultant inhibition of hydrolytic activity, than the simple methylene analogues.² On this basis, the methylene and hydroxymethylene analogues of tyrosine O-phosphate appear to be reasonable candidates to Serve as inhibitors for phosphoprotein phosphatases and alkaline phosphatase, and as probes for biological mechanisms.     

An Improved Direct Oxidation of Alkyl Halides to Aldehydes

The oxidation of alkyl chlorides and bromides with dimethyl sulfoxide has been performed in the presence of sodium iodide. This method allows a convenient one-step procedure for the preparation of aldehydes from alkyl chlorides and bromides.     

Screening Dyrk1A inhibitors by MALDI-QqQ mass spectrometry: systematic comparison to established radiometric,luminescence, and LC–UV–MS assays

Enzyme-catalyzed reactions play key roles in disease pathology, thus making them relevant subjects of therapeutic inhibitor screening experiments. Matrix-assisted laser desorption/ionization (MALDI) assays have been demonstrated to be able to replace established screening approaches. They offer increased sample throughput, but care must be taken to avoid instrumental bias from differences in ionization efficiencies. We compared a MALDI-triple-quadrupole (QqQ) method for the Dyrk1A peptide substrate woodtide to LC–MS, liquid chromatography with ultraviolet detection (LC–UV), luminescence, and radiometric assays. MALDI measurements were performed on a MALDI-QqQ instrument in the multiple-reaction monitoring mode. Different MALDI conditions were investigated to address whether matrix type, sample support, and MRM- or SIM-based detection conditions can be used to accommodate the molar responses of substrate peptide and its phosphorylated form. UV detection served as a reference method. The impact of MALDI matrix on IC₅₀ values was small, even considering that matrix preparations were used that are known to alleviate response differences. IC₅₀ values determined by MALDI were ca. 2-fold lower than those determined by LC–UV. Although MALDI generated lower ion yields for the phosphorylated peptide than for the peptide substrate, we found that a correction of compound potencies was readily possible using correction factors based on unbiased LC–UV results. A thorough method development delivered a robust assay with excellent performance (Z′ > 0.91) that was close to that seen for LC–UV.

Third-order Nonlinear Optical Properties of Octa-substituted Metal-free Phthalocyanine Thin Films

Third-order nonlinear optical susceptibility, χ⁽³⁾ of symmetrically octa-substituted metal-free phthalocyanine thin films measured by the third-harmonic generation technique are reported. The metal-free phthalocyanine has been found to show a χ⁽³⁾ (−3ω; ω,ω, ω) value as large as 7.73×10⁻¹² esu at 1.80 μm. The figure of merit, χ⁽³⁾/α, was estimated to be 4.17×10¹⁷ esu cm at 1.05 μm and 6.97×10¹⁶ esu cm at 1.65 μm. Both linear and third-order optical properties of liquid-crystalline metal-free phthalocyanines are discussed