Identification of Aminoimidazole and Aminothiazole Derivatives as Src Family Kinase Inhibitors

Src family kinases (SFKs) are a family of non‐receptor tyrosine kinases (TKs) implicated in the regulation of many cellular processes. The aberrant activity of these TKs has been associated with the growth and progression of cancer. In particular, c‐Src is overexpressed or hyperactivated in a variety of solid tumors and is most likely a strong promoting factor for the development of metastasis. Herein, the synthesis of new 4‐aminoimidazole and 2‐aminothiazole derivatives and their in vitro biological evaluation are described for their potential use as SFK inhibitors. Initially, 2‐aminothiazole analogues of dasatinib and 4‐aminoimidazole derivatives were synthesized and tested against the SFKs Src, Fyn, Lyn, and Yes. Five hits were identified as the most promising compounds, with K_i values in the range of 90–480 nm . A combination of molecular docking, homology modeling, and molecular dynamics were then used to investigate the possible binding mode of such compounds within the ATP binding site of the SFKs. Finally, the antiproliferative activities of the best candidates were evaluated against SH‐SY5Y and K562 cell lines. Compound 3 b [2‐(4‐{2‐methyl‐6‐[(5‐phenylthiazol‐2‐yl)amino]pyrimidin‐4‐yl}piperazin‐1‐yl)ethanol] was found to be the most active inhibitor.     

Oxidative Stress in Obesity: A Critical Component in Human Diseases

Obesity, a social problem worldwide, is characterized by an increase in body weight that results in excessive fat accumulation. Obesity is a major cause of morbidity and mortality and leads to several diseases, including metabolic syndrome, diabetes mellitus, cardiovascular, fatty liver diseases, and cancer. Growing evidence allows us to understand the critical role of adipose tissue in controlling the physic-pathological mechanisms of obesity and related comorbidities. Recently, adipose tissue, especially in the visceral compartment, has been considered not only as a simple energy depository tissue, but also as an active endocrine organ releasing a variety of biologically active molecules known as adipocytokines or adipokines. Based on the complex interplay between adipokines, obesity is also characterized by chronic low grade inflammation with permanently increased oxidative stress (OS). Over-expression of oxidative stress damages cellular structures together with under-production of anti-oxidant mechanisms, leading to the development of obesity-related complications. The aim of this review is to summarize what is known in the relationship between OS in obesity and obesity-related diseases.     

The Phosphoinositide 3‐Kinase Signaling Pathway is Involved in the Control of Modified Low‐Density Lipoprotein Uptake by Human Macrophages

The transformation of macrophages into lipid‐loaded foam cells is a critical early event in the pathogenesis of atherosclerosis. Both receptor‐mediated uptake of modified LDL, mediated primarily by scavenger receptors‐A (SR‐A) and CD36 along with other proteins such as lipoprotein lipase (LPL), and macropinocytosis contribute to macrophage foam cell formation. The signaling pathways that are involved in the control of foam cell formation are not fully understood. In this study, we have investigated the role of phosphoinositide 3‐kinase (PI3K) in relation to foam cell formation in human macrophages. The pan PI3K inhibitor LY294002 attenuated the uptake of modified LDL and macropinocytosis, as measured by Lucifer Yellow uptake, by human macrophages. In addition, the expression of SR‐A, CD36 and LPL was attenuated by LY294002. The use of isoform‐selective PI3K inhibitors showed that PI3K‐β, ‐γ and ‐δ were all required for the expression of SR‐A and CD36 whereas only PI3K‐γ was necessary in the case of LPL. These studies reveal a pivotal role of PI3K in the control of macrophage foam cell formation and provide further evidence for their potential as therapeutic target against atherosclerosis.     

trans Fatty Acids in Colostrum,Mature Milk and Diet of Lactating Adolescents

The purpose of this study was to investigate the trans fatty acids (TFA) content and distribution in colostrum, mature milk, and diet of adolescent mothers, after TFA declaration in food labels became mandatory in Brazil. Participants were healthy adolescents (n 54, 15–19 years, 1–90 days postpartum) practicing exclusive breastfeeding. Milk samples were collected 3 days after delivery (colostrum) and in the third month postpartum (mature milk) by hand expression. The fatty acid composition of the milk samples was determined by gas chromatography. TFA intake corresponded to 1.23 % of total energy value. Total 18:2 TFA accounted for less than 0.5 % of the energy intake. The amount of total 18:1 TFA (mean ± SEM) was 1.9 % ± 0.14 in colostrum and 1.5 % ± 0.2 in mature milk. The total content of n‐3 PUFA was inversely correlated with the total content of 18:1 TFA in colostrum. Both in colostrum and in mature milk, vaccenic acid (11t‐18:1) was found to be the most abundant 18:1 trans isomer, followed by elaidic acid (9t‐18:1), whereas rumenic acid (9c,11t‐18:2 CLA) was the predominant 18:2 trans isomer. In conclusion, the levels of TFA of industrial sources found in the mother's diet and breast milk (colostrum and mature milk) showed a decrease in relation to those observed in studies conducted prior to the TFA labeling resolution in Brazil. However, the current low intake levels of n‐3 LCPUFA and DHA content in the milk of lactating adolescents may be insufficient for supporting adequate neurological development of the infants.     

Designing Dual Transglutaminase 2/Histone Deacetylase Inhibitors Effective at Halting Neuronal Death

In recent years there has been a clear consensus that neurodegenerative conditions can be better treated through concurrent modulation of different targets. Herein we report that combined inhibition of transglutaminase 2 (TG2) and histone deacetylases (HDACs) synergistically protects against toxic stimuli mediated by glutamate. Based on these findings, we designed and synthesized a series of novel dual TG2–HDAC binding agents. Compound 3 [(E)‐N‐hydroxy‐5‐(3‐(4‐(3‐oxo‐3‐(pyridin‐3‐yl)prop‐1‐en‐1‐yl)phenyl)thioureido)pentanamide] emerged as the most interesting of the series, being able to inhibit TG2 and HDACs both in vitro (TG2 IC₅₀=13.3±1.5 μm , HDAC1 IC₅₀=3.38±0.14 μm , HDAC6 IC₅₀=4.10±0.13 μm ) and in cell‐based assays. Furthermore, compound 3 does not exert any toxic effects in cortical neurons up to 50 μm and protects neurons against toxic insults induced by glutamate (5 mm ) with an EC₅₀ value of 3.7±0.5 μm .     

Behavioral Changes in Workers of the Leaf-Cutting Ant Atta sexdens rubropilosa Induced by Chemical Components of Eucalyptus maculata Leaves

The response of Atta sexdens rubropilosa Forel workers to essential oils, epicuticular wax and hexane, dichloromethane, ethyl acetate, and methanol extracts of Eucalyptus maculata was evaluated. Hexane extracts of E. maculata interfered with the recognition mechanism among workers. The main active compounds identified from this plant were the sesquiterpenes elemol and beta-eudesmol. These compounds may be responsible for the resistance of this species to ant attack.     

A DNA Methyltransferase Modulator Inspired by Peyssonenyne Natural Product Structures

A novel epigenetic modulator that displays a DNMT1 inhibition and DNMT3A activation profile was characterized (compound 8 ). This compound is a derivative of palmitic acid that incorporates the putative reactive functional group (diynone) of the peyssonenyne natural products. Other analogues containing the diynone or an acetoxyenediyne did not show the same biological profile. In U937 human leukemia cells, diynone 8 induced cell differentiation and apoptosis, which correlated with the expression of Fas protein. Very surprisingly, diynone 8 was toxic to normal human fibroblasts (BJ) and mouse embryo fibroblasts (MEF), but not to immortalized human fibroblasts (BJEL); this unique effect was not observed with the classical DNMT inhibitor 5‐azacytidine. Therefore, compound 8 interferes in a very specific manner with signaling pathways, the activities of which differ between normal and immortalized cell types. This toxicity is reminiscent of the effects of Dnmt1 ablation on mouse fibroblasts. In fact, some of the genes deregulated by the loss of Dnmt1 are similarly deregulated by 8 , but not by the DNMT inhibitor SGI‐1027.     

Design, synthesis, and biological evaluation of 2-aminobenzanilide derivatives as potent and selective HDAC inhibitors

Epigenetic regulation is an essential process for the normal functioning of genes. Therefore, targeting epigenetic dysregulation in cancer may be a valid therapeutic approach for the treatment of this severe disease. Histone deacetylases (HDACs) are enzymes involved in the regulation of epigenetic post-translational modifications; because they are overexpressed in many types of cancer, HDACs are valuable targets for the development of new anticancer agents. A large series of 2-aminobenzanilides linked at the 4'-position to α-amino acid amides, arenes, and heteroarenes through a methylene bridge were designed, synthesized, and tested as novel HDAC inhibitors. Several compounds showed IC(50) values in the two-digit nanomolar range in hrHDAC1 inhibition assays, lower than that of the reference compound MS-275. They also showed interesting selectivity profiles, as confirmed by western blot assays.     

Synthesis and Biological Evaluation of CTP Synthetase Inhibitors as Potential Agents for the Treatment of African Trypanosomiasis

Acivicin analogues with an increased affinity for CTP synthetase (CTPS) were designed as potential new trypanocidal agents. The inhibitory activity against CTPS can be improved by increasing molecular complexity, by inserting groups able to establish additional interactions with the binding pocket of the enzyme. This strategy has been pursued with the synthesis of α‐amino‐substituted analogues of Acivicin and N1‐substituted pyrazoline derivatives. In general, there is direct correlation between the enzymatic activity and the in vitro anti‐trypanosomal efficacy of the derivatives studied here. However, this cannot be taken as a general rule, as other important factors may play a role, notably the ability of uptake/diffusion of the molecules into the trypanosomes.     

Catalytic activity of supported metal particles for sulfuric acid decomposition reaction

Production of hydrogen by splitting of water in the thermochemical sulfur-based cycles that employs the catalytic decomposition of sulfuric acid into SO₂ and O₂ is of considerable interest. However, all of the known catalytic systems studied to date that consist of metal particles on oxide substrates deactivate with time on stream. To develop an understanding of the factors that are responsible for catalyst activity, we investigate the fresh activity of several platinum group metals (PGM) catalysts, including Pd, Pt, Rh, Ir, and Ru supported on titania at 850 °C and perform an extensive theoretical study (density-functional-theory-based first-principles calculations and computer simulations) of the activity of the PGM nanoparticles of different size and shape positioned on TiO₂ (rutile and anatase) and Al₂O₃ (γ- and η-alumina) surfaces. The activity and deactivation of the catalytic systems are defined by (i) the energy barrier for the detachment of O atoms from the SO_n (n = 1, 2, 3) species, and (ii) the removal rate of the products of the sulfuric acid decomposition (atomic O, S, and the SO_n species) from metal nanoparticles. We show that these two nanoscale features collectively result in the observed experimental behavior. The removal rate of the reaction products is always lower than the SO_n decomposition rates. The relation between these two rates explains why the “softer” PGM nanoparticles (Pd and Pt) exhibit the highest initial catalytic activity.