Het(aryl)isatin to het(aryl)aminoindoline scaffold hopping: A route to selective inhibitors of matrix metalloproteinases

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endoproteases known to exert multiple regulatory roles in tumor progression. A variety of chemical classes have been explored for targeting individual MMP isoforms. In the present study, we further developed our isatin based scaffold BB0223107 capable of binding to and inactivating MMP-2 in a zinc-independent manner (Agamennone et al., 2016). Forty four new compounds were synthesized based on the modified BB0223107. All compounds were tested in enzyme inhibition assays against MMP-2, ?8 and ?13. SAR studies demonstrated that 5-het(aryl)-3-aminoindolin-2-ones (37–39) were active toward MMP-2 and MMP-13. The most potent compounds 33 and 37 displayed an IC₅₀ of 3 µM against MMP-13 and showed a negligible activity toward MMP-8; almost all new compounds were inactive toward MMP-8. Replacement of the isatin ring with a biaryl system (compound 33) did not decrease the potency against MMP-13 but reduced the selectivity. Structure-based computational studies were carried out to rationalize the inhibitory activity data. The analysis of binding geometries confirmed that all fragments occupied the S1′ site in the three enzymes while no ligand was able to bind the catalytic zinc ion. To the best of our knowledge, this is the first example of 3-aminoindolin-2-one-based MMP inhibitors that, based on the computer modeling study, do not coordinate the zinc ion. Thus, the het(aryl)-3-aminoindolin-2-one derivatives emerge as a drug-like and promising chemotype that, along with the hetaryl variations, represents an alternative and thrifty tool for chemical space exploration aimed at MMP inhibitor design.     

Mossbauer investigations of corrosion environment influence on Fe valence states in oxide films of zirconium alloys

Mössbauer investigations about iron atom redistribution in oxide films of zirconium alloys subjected to corrosion at 500°C in pure oxygen and water pair have been analysed. The alloys were also subjected to autoclave conditions at a pressure of 10.0 MPa and autoclave conditions at 350°C and at a pressure of 16.8 MPa, using distilled water and water with additives of lithium and fluorine. It is shown that, depending on the corrosion environment, various compounds of iron, such as α-Fe₂O₃, Fe₃O₄, and FeO, as solid solutions of iron in ZrO₂ are formed in oxide films.     

New stereoselective synthesis of the peptidic aminopeptidase inhibitors bestatin, phebestin and probestin

Peptidic aminopeptidase inhibitors, bestatin, phebestin and probestin have been prepared by stereo- and regiocontrolled reactions from a common α,β-epoxy ester precursor.     

A new approach towards peptidosulfonamides: synthesis of potential inhibitors of bacterial peptidoglycan biosynthesis enzymes MurD and MurE

Peptidosulfonamides are an emerging group of peptidomimetics with a variety of applications in medicinal chemistry. We present a novel approach to the synthesis of peptidosulfonamides, and apply it to a series of new potential inhibitors of the bacterial peptidoglycan biosynthesis enzymes MurD and MurE. The synthesis was conducted via N-phthalimido β-aminoethanesulfonyl chlorides, which are new building blocks for the synthesis of peptidosulfonamides. In the most crucial step, sulfonic acids or their sodium salts were converted into the corresponding sulfonyl chlorides using an excess of either SOCl₂ or SOCl₂/DMF, and then coupled to the C-protected amino acid. None of the compounds significantly inhibited MurD, however, some inhibited MurE; one had an IC₅₀ below 200 μM, which constitutes a promising starting point for further development. Molecular modelling simulations were performed on two analogues to investigate the absence of inhibitory activity of the sulfonamide compounds on MurD.     

The origin of the formation of cavities in galvanized coatings

The role of water‐soluble corrosion products on galvanized wires was examined. The samples used were industrial hot‐dip galvanized wires, which were exposed to the open air under all weather conditions for a relatively short time (6 and 12 months), in an urban environment close to the sea. The samples were studied by different methods, i.e. scanning electron microscopy (SEM), transmission electron microscopy (TEM), X‐ray diffraction (XRD) and optical microscopy (OM). Several phases were detected because of the galvanization procedure and the steel substrate. Furthermore, phases which were formed as a result of the reaction of zinc with the atmosphere were also detected. These were oxides like ZnO, carbonates like ZnCO₃ and hydrated Zn and Fe sulfates. Their presence influences the corrosion resistance of the wires, which finally, strongly depends on the solubility of the wires in water. The SO₄^2? compounds especially are very soluble and consequently are easily removed from the coating surface, leading to its degradation by the formation of cavities. In any case, their presence, even after a short period of exposure, implies that the coating is highly affected by the atmosphere of the modern city. Copyright © 2006 John Wiley & Sons, Ltd.     

Current methods for site-directed structure generation

Summary There has been a rapid growth of interest in techniques for site-directed drug design, fuelled by the increasing availability of structural models of proteins of therapeutic importance, and by studies reported in the literature showing that potent chemical leads can be obtained by these techniques. Structure generation programs offer the prospect of discovering highly original lead structures from novel chemical families. Due to the fact that this technique is more-or-less still in its infancy, there are no case studies available that demonstrate the use of structure generation programs for site-directed drug design. Such programs were first proposed in 1986, and became commercially available in early 1992. They have shown their ability to reproduce, or suggest reasonable alternatives for, ligands in well-defined binding sites. This brief review will discuss the recent advances that have been made in the field of site-directed structure generation.     

Surface-enhanced Raman scattering study of polymer on metals. III. Chemisorbed polybenzimidazole and its corrosion-inhibiting properties at high temperature

Chemisorption of polybenzimidazole on silver and copper etched with nitric acid has been observed by surface-enhanced Raman scattering (SERS). The polymer is found to react chemically with silver, forming a complexed film on the surface. The SERS spectra show that polybenzimidazole film inhibits oxidation of the metal at high temperature, unlike chemisorbed benzimidazole, benzotriazole, and poly(4-vinyl pyridine). © 1992 John Wiley & Sons, Inc.     

稀土及杂质元素对ZA27合金晶间腐蚀的影响

为了从本质上了解杂质与稀土元素对锌铝合金晶间腐蚀的影响 ,探索抑制合金晶间腐蚀的有效途径 ,依据晶界的大角度重位点阵理论编制出相应计算机软件 ,建立含稀土、杂质及 η相颗粒的α相大角度晶界原子集团模型 ,采用递归法计算了α相晶界间的电荷转移 ,由此讨论了杂质 (Pb、Sn、Cd)及稀土元素 (La、Y)对Zn、Al电极电位的影响 .结果表明 ,杂质Pb、Sn、Cd增大原子间的电荷转移量 ,提高Zn、Al电极电位差 ,加速合金的腐蚀 ,稀土元素减小原子间的电荷转移量 ,降低Zn、Al电极电位差 ,具有抑制晶间腐蚀的作用 .     

Inhibitors of biotin biosynthesis as potential herbicides

Isosteric derivatives and analogues of the 7-keto-8-aminopelargonic acid (KAPA), 7,8-diaminopelargonic acid (DAPA) and desthiobiotin (DTB) vitamer intermediates involved in the biosynthetic pathway of biotin were prepared and evaluated as potential herbicides. The most active compound was desmethyl-KAPA which displayed a GR₅₀ (concentration of the active compound that causes a 50% growth inhibition) value of 8 ppm, where values <50 ppm are considered herbicidal. Other KAPA analogs where the terminal Me group was replaced by bulkier substituents such as Et, i-Pr and HOCH₂ showed moderate activity.     

The structure-activity relationship of inhibitors of serotonin uptake and receptor binding

Summary An analysis of five different datasets of inhibitors of serotonin uptake has yielded quantitative structure/ activity relationships (QSARs) which delineate the role of steric and hydrophobic properties essential for inhibition by phenylethylamine-type analogues.