Salicylaldoxime derivatives as new leads for the development of carbonic anhydrase inhibitors

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Antiproliferative oxime derivatives that inhibit glucose transporter 1 (GLUT1) in cancer cells

The Warburg effect, consisting in alterations of the glucose metabolism in cancer cells, where glucose mostly undergoes glycolysis with production of lactate, is currently being considered as one of the most intriguing hallmarks of cancer [1]. Therefore, the discovery of new agents able to block the glycolytic processes in tumor cells holds promise for developing relatively nontoxic anticancer treatments [2]. In terms of energy (ATP) production, glycolysis is dramatically less efficient than oxidative phosphorylation (OXPHOS). In fact, most normal cells rely on OXPHOS for glucose degradation, since they are generally well-oxygenated. On the contrary, invasive tumor tissues are often exposed to more-or-less transient hypoxia, which cannot guarantee the proper functioning of OXPHOS. Under these hypoxic conditions glycolysis leading to lactate production is mainly preferred, since it does not depend on oxygen availability. However, due to the lower efficiency of the glycolytic process, cancer cells commonly show a remarkably high glucose uptake, which is supported by the overexpression of the glucose transporters (GLUTs). GLUT1 is one of the most commonly transporters that are overexpressed by cancer cells and, therefore, represent a potential target for selectively hitting them [3], although only a very limited number of GLUT1-inhibitors have been reported so far [4]. On the basis of an analysis of the pharmacophoric features displayed by some previously reported GLUT1-inhibitors, we have identified a series of oxime derivatives [5] as potentially active on this transporter. A preliminary screening of these compounds in H1299 lung cancer cells demonstrated that some of them are able to effectively counteract glucose uptake and cell growth, displaying IC50 values in the low micromolar range. We have then developed a new computational model of GLUT1, which provided us with valuable clues about the possible binding site and the most important interactions occurring with some representative oxime derivatives and GLUT1. These indications may prove to be very valuable for the future development of novel potent and selective GLUT1-inhibitors. References: [1] Hanahan, D.; Weinberg, R. A. Cell 2011, 144, 646-674. [2] Granchi, C.; Minutolo, F. ChemMedChem 2012, 7, 1318-1350. [3] Rastogi, S.; Banerjee, S.; Chellappan, S.; Simon, G. R. Cancer Lett. 2007, 257, 244-251. [4] Liu, Y.; Cao, Y.; Zhang, W.; Bergmeier, S.; Qian, Y.; Akbar, H.; Colvin, R.; Ding, J.; Tong, L.; Wu, S.; Hines, J.; Chen, X. Mol. Cancer Ther. 2012, 11, 1672-1682, and references therein. [5] Minutolo, F.; Bertini, S.; Granchi, C.; Marchitiello, T.; Prota, G.; Rapposelli, S.; Tuccinardi, T.; Martinelli, A.; Gunther, J. R.; Carlson, K. E.; Katzenellenbogen, J. A.; Macchia, M. J. Med. Chem. 2009, 52, 858-867

Design, synthesis, ADME and biological evaluation of benzylpiperidine and benzylpiperazine derivatives as novel reversible monoacylglycerol lipase (MAGL) inhibitors.

The degradation of the endocannabinoid 2-arachidonoylglycerol is mediated by the enzyme monoacylglycerol lipase (MAGL), thus generating arachidonic acid, the precursor of prostaglandins and other pro-inflammatory mediators. MAGL also contributes to the hydrolysis of monoacylglycerols into glycerol and fatty acids in peripheral body districts, which may act as pro-tumorigenic signals. For this reason, MAGL inhibitors have been considered as interesting therapeutic agents for their anti-nociceptive, anti-inflammatory, antioxidant and anti-cancer properties. So far, only a limited series of reversible MAGL inhibitors, which are devoid of side effects shown by irreversible inhibitors in animal models, have been reported. Here we optimized a class of benzylpiperidine and benzylpiperazine-based compounds for a reversible MAGL inhibition. The best MAGL inhibitors of this class, compounds 28 and 29, showed a very good inhibition potency, both on the isolated enzyme and in U937 cells, as confirmed by molecular modeling studies that predicted their binding mode into the MAGL active site. Both compounds are characterized by a high selectivity for MAGL versus other serine hydrolases including enzymes of the endocannabinoid system, as confirmed by ABPP experiments in mouse brain membranes. Moreover, very good properties concerning ADME parameters and low in vivo toxicity have been observed for both compounds

Estrogen receptor ligands: a patent review update

Introduction: The role of estrogens is mostly mediated by two nuclear receptors (ERα and ERβ) and a membrane-associated G-protein (GPR30 or GPER), and it is not limited to reproduction, but it extends to the skeletal, cardiovascular and central nervous systems. Various pathologies such as cancer, inflammatory, neurodegenerative and metabolic diseases are often associated to dysfunctions of the estrogenic system. Therapeutic interventions by agents that affect the estrogenic signaling pathway might be useful in the treatment of many dissimilar diseases. Areas covered: The massive chemodiversity of ER-ligands, limited to patented small molecules, is herein reviewed. The reported compounds are classified on the basis of their chemical structures. Nonsteroidal derivatives, which mostly consist in diphenolic compounds, are further segregated into chemical classes based on their central scaffold. Expert opinion: Estrogens have been used for almost a century and their earlier applications have concerned interventions in the female reproductive functions, as well as the treatment of some estrogen-dependent cancers and osteoporosis. Since the discovery of ERβ in 1996 the patent literature has started to pay a progressively increasing attention to this newer receptor subtype, which holds promise as a target for new indications, most of which still need to be clinically validated

Effectiveness of differentiation inducers in combination on human neuroblastoma cells in vitro

The effects of epirubicin and retinoic acid (RA) as differentiation inducing agents on human neuroblastoma cell lines were investigated. We have compared the response of neuroblastoma cells to epirubicin alone, to RA alone and to combined treatment, with respect to neuritic processes outgrowth, acethylcholinesterase activity, growth inhibition and antigenic expression. The obtained data indicate that the combination of the two agents is able to produce a synergistic effect on differentiation and on growth inhibition

Impact of Saccharomyces cerevisiae Strains on Health-Promoting Compounds in Wine

Moderate wine consumption is associated with human health benefits (reduction of cardiovascular risk and neurodegenerative diseases, decrease of onset of certain cancers) attributed to a series of bioactive compounds, mainly polyphenols, with antioxidant power capable of counteracting the negative action of free radicals. Polyphenols are naturally present in the grapes, but an additional amount originates during winemaking. The aim of this work was to assess the ability of four commercial and two indigenous Saccharomyces cerevisiae strains to produce bioactive compounds (tyrosol, hydroxytyrosol, tryptophol, melatonin and glutathione) during alcoholic fermentation. In order to exclude the fraction of antioxidant compounds naturally occurring in grapes, the strains were inoculated in a synthetic must. At the end of fermentation the bioactive compounds were analysed by High-Performance Liquid Chromatography, while antioxidant activity was measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Moreover, freeze-dried samples, originating from the experimental wines, were used to perform ex-vivo assays on cultured cells (RAW 264.7 murine macrophages) with the aim to evaluate their antioxidant and anti-inflammatory activities. The results indicated that the production of the considered bioactive compounds is a strain-specific property; therefore, the different yeast strains utilized during fermentation have different capabilities to modify the antioxidant and anti-inflammatory properties of the wine