Phosphotyrosyl peptides and analogues as substrates and inhibitors of purple acid phosphatases

Purple acid phosphatases are metal-containing hydrolases. While their precise biological role(s) is unknown, the mammalian enzyme has been linked in a variety of biological circumstances (e.g., osteoporosis) with increased bone resorption. Inhibition of the human enzyme is a possible strategy for the treatment of bone-resorptive diseases such as osteoporosis. Previously, we determined the crystal structure of pig purple acid phosphatase to 1.55 Angstrom and we showed that it is a good model for the human enzyme. Here, a study of the pH dependence of its kinetic parameters showed that the pig enzyme is most efficient at pH values similar to those encountered in the osteoclast resorptive space. Based on the observation that phosphotyrosine-containing peptides are good substrates for pig purple acid phosphatase, peptides containing a range of phosphotyrosine mimetics were synthesized. Kinetic analysis showed that they act as potent inhibitors of mammalian and plant purple acid phosphatases, with the best inhibitors exhibiting low micromolar inhibition constants at pH 3-5. These compounds are thus the most potent organic inhibitors yet reported for the purple acid phosphatases. (C) 2004 Published by Elsevier Inc.

The corrosion inhibition mechanism of new rare earth cinnamate compounds — electrochemical studies

A combination of linear polarisation resistance (LPR) and cyclic potentiodynamic polarisation (CPP) measurements demonstrated that the lanthanum-4 hydroxy cinnamate compound could inhibit both the cathodic and anodic corrosion reactions on mild steel surfaces exposed to 0.01 M NaCl solutions. However, the dominating response was shown to vary with inhibitor concentration. At the concentrations for which the highest level of protection was achieved, both REM-4 hydroxy cinnamate (REM being lanthanum and mischmetal) displayed a strong anodic behaviour for mild steel and their inhibition performance, including their resistance against localised attack, improved with time.

Electrochemical impedance spectroscopy (EIS) measurements and modelling were carried out so as to propose a simple electrical model and correlate the extracted parameters to the inhibition mechanism put forward for REM-cinnamate based compounds. The results supported the high corrosion inhibition performance of the compounds as well as the build-up of a protective film with time. Based on a two-layer model the results suggested that the upper layer of the inhibitor film seemed to offer less resistance to the diffusion of electrochemically active species than the highly resistive inner layer at the film/metal interface.

Corrosion mitigation of mild steel by new rare earth cinnamate compounds

Corrosion rate measurements based on weight loss (i.e., mild steel immersed for seven days in 0.01 M NaCl) and linear polarization resistance (LPR) techniques have shown that even low concentrations (200 ppm) of cerium and lanthanum cinnamates are able to significantly inhibit corrosion. Of all the compounds investigated in this work Ce(4-methoxycinnamate)3· 2 H2O and La(4-methoxycinnamate)3· 2 H2O compounds exhibited the greatest inhibition and, in comparison with the component inhibitors, a synergy was clearly observed. The mechanism of corrosion inhibition was investigated using cyclic potentiodynamic polarization (CPP) measurements. The results suggest that La(4-nitrocinnamate)3· 2 H2O and Ce(4-methoxycinnamate)3· 2 H2O behave as mixed inhibitors and improve the resistance of steel against localized attack.

Amperometric biosensor for tyrosinase inhibitors in a pure organic phase

The determination of benzoic acid, thiourea and 2-mercaptoethanol in three pure organic solvents, viz., chloroform, chlorobenzene and 1,2-dichlorobenzene, by using an amperometric cryohydrogel tyrosinase biosensor is described. Measurements were carried out with phenol as the enzyme substrate. Kinetic parameters (K-i and I-50) were determined in the three solvents for various inhibitors. The sensor showed the most sensitive measurements to these inhibitors in pure chloroform. The solvent-induced deviation of the biosensor to thiourea was evaluated by means of Hill coefficients. The smallest deviation as observed in 1,2-dichlorobenzene, owing to the high hydrophobicity of this solvent. The nature of the inhibition process and its reversibility mere also examined.

Electrochemical and quantum chemical assessment of two organic compounds from pyridine derivatives as corrosion inhibitors for mild steel in HCl solution under stagnant condition and hydrodynamic flow

 In this study, the inhibitive performance of two pyridine derivatives as corrosion inhibitors for mild steel was examined under stagnant condition and hydrodynamic flow in HCl solution at 25. °C. Potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) techniques were employed. To explore the inhibitors adsorption mechanism, Langmuir isotherm and quantum chemical studies were used. The results of electrochemical measurements show that the inhibitor concentration has a positive effect on its efficiency while for hydrodynamic condition, it is vice versa. Corrosion attack morphologies were observed at stagnant and hydrodynamic conditions to verify qualitatively the results obtained by electrochemical methods. © 2013 Elsevier Ltd.

Multifunctional rare earth organic corrosion inhibitors

All rights reserved.Chromium (VI) compounds are commonly used in paint systems to provide corrosion protection, particularly for aerospace alloys. These compounds are toxic, carcinogenic and environmentally detrimental, therefore alternatives that are safe, environmentally benign and meet or exceed current levels of corrosion protection are vital. Multifunctional rare earth organic compounds incorporate known inhibitor species, achieving synergistic inhibition in corrosive environments. The mechanism, efficiency and surface interactions of these complexes are explored. The complexes were effective inhibitors for steel and aluminium alloys, through mixed inhibition. Advantages and limitations of these inhibitor complexes, along with applications and future research direction, are discussed.

Synthesis of novel inhibitors blocking Wnt signaling downstream of β-Catenin

Large scale screening of libraries consisting of natural and small molecules led to the identification of many small molecule inhibitors repressing Wnt/β-Catenin signaling. However, targeted synthesis of novel Wnt pathway inhibitors has been rarely described. We developed a modular and expedient way to create the aromatic ring system with an aliphatic ring in between. Our synthesis opens up the possibility, in principle, to substitute all positions at the ring system with any desired substituent. Here, we tested five different haloquinone analogs carrying methoxy- and hydroxy-groups at different positions. Bona fide Wnt activity assays in cell culture and in Xenopus embryos revealed that two of these compounds act as potent inhibitors of aberrant activated Wnt/β-Catenin signaling.

Synthesis, Reactivity and Biological Activity of 17β-HSD1 Inhibitors Based on a Thieno[2,3-d]pryrimidin-4(3H)-one Core

Breast cancer is the most common cancer in women in Western countries. In the early stages of development most breast cancers are hormone-dependent, and estrogens, especially estradiol, have a pivotal role in their development and progression. One approach to the treatment of hormone-dependent breast cancers is to block the formation of the active estrogens by inhibiting the action of the steroid metabolising enzymes. 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is a key enzyme in the biosynthesis of estradiol, the most potent female sex hormone. The 17beta-HSD1 enzyme catalyses the final step and converts estrone into the biologically active estradiol. Blocking 17beta-HSD1 activity with a specific enzyme inhibitor could provide a means to reduce circulating and tumour estradiol levels and thus promote tumour regression. In recent years 17beta-HSD1 has been recognised as an important drug target. Some inhibitors of 17beta-HSD1 have been reported, however, there are no inhibitors on the market nor have clinical trials been announced. The majority of known 17beta-HSD1 inhibitors are based on steroidal structures, while relatively little has been reported on non-steroidal inhibitors. As compared with 17beta-HSD1 inhibitors based on steroidal structures, non-steroidal compounds could have advantages of synthetic accessibility, drug-likeness, selectivity and non-estrogenicity. This study describes the synthesis of large group of novel 17beta-HSD1 inhibitors based on a non-steroidal thieno[2,3-d]pyrimidin-4(3H)-one core. An efficient synthesis route was developed for the lead compound and subsequently employed in the synthesis of thieno[2,3-d]pyrimidin-4(3H)-one based molecule library. The biological activities and binding of these inhibitors to 17beta-HSD1 and, finally, the quantitative structure activity relationship (QSAR) model are also reported. In this study, several potent and selective 17beta-HSD1 inhibitors without estrogenic activity were identified. This establishment of a novel class of inhibitors is a progressive achievement in 17beta-HSD1 inhibitor development. Furthermore, the 3D-QSAR model, constructed on the basis of this study, offers a powerful tool for future 17beta-HSD1 inhibitor development. As part of the fundamental science underpinning this research, the chemical reactivity of fused (di)cycloalkeno thieno[2,3-d]pyrimidin-4(3H)-ones with electrophilic reagents, i.e. Vilsmeier reagent and dimethylformamide dimethylacetal, was investigated. These findings resulted in a revision of the reaction mechanism of Vilsmeier haloformylation and further contributed to understanding the chemical reactivity of this compound class. This study revealed that the reactivity is dependent upon a stereoelectronic effect arising from different ring conformations.

Development and characterization of lysine based tripeptide analogues as inhibitors of Sir2 activity

Sirtuins are NAD(+) dependent deacetylases that modulate various essential cellular functions. Development of peptide based inhibitors of Sir2s would prove useful both as pharmaceutical agents and as effectors by which downstream cellular alterations can be monitored. Click chemistry that utilizes Huisgen's 1,3-dipolar cycloaddition permits attachment of novel modifications onto the side chain of lysine. Herein, we report the synthesis of peptide analogues prepared using click reactions on N epsilon-propargyloxycarbonyl protected lysine residues and their characterization as inhibitors of Plasmodium falciparum Sir2 activity. The peptide based inhibitors exhibited parabolic competitive inhibition with respect to acetylated-peptide substrate and parabolic non-competitive inhibition with NAD(+) supporting the formation of EI2 and E.NAD(+).I-2 complexes. Cross-competition inhibition analysis with the non-competitive inhibitor nicotinamide (NAM) ruled out the possibility of the NAM-binding site being the second inhibitor binding site, suggesting the presence of a unique alternate pocket commodating the inhibitor. One of these compounds was also found to be a potent inhibitor of the intraerythrocytic growth of P. falciparum with 50% inhibitory concentration in the micromolar range.