Phosphopeptide selective coordination complexes as promising SRC homology 2 domain mimetics

Src Homology 2 (SH2) domains are the paradigm of phosphotyrosine (pY) protein recognition modules and mediate numerous cancer-promoting protein-protein complexes. Effective SH2 domain mimicry with pY-binding coordination complexes offers a promising route to new and selective disruptors of pY-mediated protein-protein interactions. We herein report the synthesis and in vitro characterization of a library of coordination complex SH2 domain proteomimetics. Compounds were designed to interact with phosphopeptides via a two-point interaction, principally with pY, and to make secondary interactions with pY+2/3, thereby achieving sequence-selective discrimination. Here, we report that lead mimetics demonstrated high target phosphopeptide affinity (K(a) ～ 10(7) M(-1)) and selectivity. In addition, biological screening in various tumor cells for anticancer effects showed a high degree of variability in cytotoxicity among receptors, which supported the proposed two-point binding mode. Several receptors potently disrupted cancer cell viability in breast cancer, prostate cancer, and acute myeloid leukemia cell lines.     

Rank Tests Based on Exceeding Observations

Rank tests based on the maximum number of exceeding observations for several standard nonparametric hypotheses are proposed. An approach to constructing nonparametric rank tests via metrics on the permutation group is used. The test statistics are based on a metric induced by Chebyshev's norm.     

A “Discretization” Technique for the Solution of ODEs II

A functional analytic technique was recently presented for finding discrete equivalent counterparts of initial value problems of ODEs and obtaining their real analytic solutions. In the current paper, this technique is extended to boundary value problems of ODEs and to the complex solutions of ODEs. In order to demonstrate this technique, it is applied to the classic Blasius problem of fluid mechanics. Apart from its real solution, its complex solution is also studied. The obtained results indicate that the complex Blasius function exhibits an oscillatory behavior and strengthen a conjecture regarding its singularities in the complex plane.     

Existence and uniqueness of solutions in H1(Δ) of a general class of non-linear functional equations

A functional analytic method is used to prove the existence and the uniqueness of a solution in the Banach space H₁(Δ) of a general class of non-linear functional equations. This general class includes some specific functional equations studied recently. Our results simplify and improve the existing results for these specific equations. Moreover, for one of them, we give an answer to an open problem.     

Boiling-induced changes in the mechanism of diglyme radiolysis

Boiling intensifies the radiolytic conversion of diglyme since it stimulates the cleavage of the C–O bonds in the excited molecules and the primary radical cations, enhances the radical exchange reactions, and weakens the diglyme regeneration reactions.

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Vibrational excitation and relaxation of five polyatomic molecules in an electrical discharge

Vibrational excitation and relaxation of five linear polyatomic molecules, OCS, OC3S, HC3N, HC5N, and SiC2S, have been studied by Fourier transform microwave spectroscopy in a supersonic expansion after the application of a low-current dc electric discharge. For each chain, the populations in bending and stretching modes have been characterized as a function of the applied discharge current; for stable OCS and HC3N, vibrational populations were studied as well in the absence of a discharge. With no discharge present the derived vibrational temperatures are slightly below T, the temperature of the gas before the supersonic expansion (i.e., 300 K). In the presence of the discharge, vibrational excitation occurs via inelastic collisions with the electrons and the vibrational temperatures rise as the applied current increases. Global vibrational relaxation is governed by rapid vibration-vibration (VV) energy transfer and slow vibration-translation (VT) energy transfer. The latter process is rate-determining and depends primarily on the wave number of the vibration. Vibrational modes with wave numbers near and below kT/hc (where T = 300 K and kT/hc-210 cm(-1)) are efficiently cooled by VT transfer because a sufficient number of collisions occur in the initial stages of the supersonic expansion. Vibrational modes with wave numbers around 450 cm(-l) appear to be inefficiently cooled in the molecular beam; at these energies VV and VT rates are probably comparable. For high-frequency vibrations, VV energy transfer dominates. For the longer chains OC3S and HC5N, higher-lying modes are generally not detectable and vibrational temperatures of most lower-lying modes were found to be lower than those of OCS and HC3N, suggesting that as the size of the molecules increases, intermode VV transfer becomes more efficient, plausibly due to the higher density of vibrational levels. New high resolution spectroscopic data have been obtained for several vibrationally excited states of OC3S, HC3N, and HC5N. Rotational lines of the 13C and 15N isotopic species of HC5N have been measured, yielding improved rotational and centrifugal distortion constants; 14N nitrogen quadrupole coupling constants for the isotopic species of HC5N with 13C have been determined for the first time.     

Positive lists of cosmetic ingredients: Analytical methodology for regulatory and safety controls – A review

Cosmetic products placed on the market and their ingredients, must be safe under reasonable conditions of use, in accordance to the current legislation. Therefore, regulated and allowed chemical substances must meet the regulatory criteria to be used as ingredients in cosmetics and personal care products, and adequate analytical methodology is needed to evaluate the degree of compliance. This article reviews the most recent methods (2005–2015) used for the extraction and the analytical determination of the ingredients included in the positive lists of the European Regulation of Cosmetic Products (EC 1223/2009): comprising colorants, preservatives and UV filters. It summarizes the analytical properties of the most relevant analytical methods along with the possibilities of fulfilment of the current regulatory issues. The cosmetic legislation is frequently being updated; consequently, the analytical methodology must be constantly revised and improved to meet safety requirements. The article highlights the most important advances in analytical methodology for cosmetics control, both in relation to the sample pretreatment and extraction and the different instrumental approaches developed to solve this challenge.     

Transamidation reactions of 2-(2-sulfonylguanidino)acetamides

The reactivity of a series of sulfonylguanidinoacetamides 2A-E towards amines is reported. Guanidinoacetamides 2A-C, containing the arylsulfonylimino moiety, undergo a facile transamidation to give substituted carboxamides 4A-C, through the imidazolidinone intermediate 3. Acetamide 2D, having a methanesulfonylimino substituent, affords the imidazolidinone 3D and no transamidated carboxamides 4 are detected. In the case of guanidinoacetamide 2E, with a p-nitrobenzenesulfonylimino substituent, a Smiles rearrangement was observed.     

Nanoparticles derived from amphiphilic γ-cyclodextrins

Three alkylcarbonates of γ-cyclodextrin, i.e. hexyl, octyl and dodecylcarbonate, were synthesized and characterized, with the goal of formulating solid nanoparticles. The series of alkylcarbonates showed amphiphilic properties and were capable of forming micelles and nanoparticles. Blank and drug-loaded alkylcarbonate nanoparticles were prepared with each alkylcarbonate, using the solvent injection technique. Progesterone was chosen as model drug. The sizes of both unloaded and loaded nanoparticles were in the 80–200 nm range, with narrow size distribution and spherical shape, as shown by TEM analysis. The zeta potentials of unloaded nanoparticles were in the −20 to −24.0 mV range, and were slightly decreased in loaded nanoparticles. Drug-loading capacity was good; DSC analysis did not detect the progesterone melting peak, indicating the drug had interacted with the cyclodextrin alkylcarbonates. In vitro release kinetics of progesterone from the three types of nanoparticles were slow. These results indicate that γ-CD alkylcarbonate nanoparticles might be used as prolonged drug delivery system.