One pot-like regiospecific access to 1-aryl-1H-pyrazol-3(2H)-one derivatives and evaluation of the anticancer activity

A set of variously substituted 1-arylpyrazol-3-one derivatives, including the di-ortho-aryl substituted ones, was synthesized as new potential anticancer compounds. To fulfill this aim, herein a regiospecific synthesis was proposed utilizing a new revisited one pot procedure, starting from commercial anilines and easily accessible 2,5-dimethyl-furan-3-one. In the course of the sequential ordered steps, in some cases, a nitro group displacement by chlorine took place to a minor extent. The in vitro screening against the full panel of ~60 human cancer cell lines (NCI) showed a moderate, but promising selective antiproliferative activity against the UO31 renal tumor cell line, only in compounds with the introduction on the phenyl moiety of a -CF3 or two Cl groups

Spectroscopic and in silico studies on the interaction of substituted pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one derivatives with c-myc g4-dna

Herein we describe a combined experimental and in silico study of the interaction of a series of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives (PBTs) with parallel G-quadruplex (GQ) DNA aimed at correlating their previously reported anticancer activities and the stabilizing effects observed by us on c-myc oncogene promoter GQ structure. Circular dichroism (CD) melting experiments were performed to characterize the effect of the studied PBTs on the GQ thermal stability. CD measurements indicate that two out of the eight compounds under investigation induced a slight stabilizing effect (2–4 °C) on GQ depending on the nature and position of the substituents. Molecular docking results allowed us to verify the modes of interaction of the ligands with the GQ and estimate the binding affinities. The highest binding affinity was observed for ligands with the experimental melting temperatures (Tms). However, both stabilizing and destabilizing ligands showed similar scores, whilst Molecular Dynamics (MD) simulations, performed across a wide range of temperatures on the GQ in water solution, either unliganded or complexed with two model PBT ligands with the opposite effect on the Tms, consistently confirmed their stabilizing or destabilizing ability ascertained by CD. Clues about a relation between the reported anticancer activity of some PBTs and their ability to stabilize the GQ structure of c-myc emerged from our study. Furthermore, Molecular Dynamics simulations at high temperatures are herein proposed for the first time as a means to verify the stabilizing or destabilizing effect of ligands on the GQ, also disclosing predictive potential in GQ-targeting drug discovery

Antimicrobial activity of aztreonam in combination with old and new β-lactamase inhibitors against mbl and esbl co-producing gram-negative clinical isolates: Possible options for the treatment of complicated infections

none14noMetallo-β-lactamases (MBLs) are among the most challenging bacterial enzymes to over-come. Aztreonam (ATM) is the only β-lactam not hydrolyzed by MBLs but is often inactivated by co-produced extended-spectrum β-lactamases (ESBL). We assessed the activity of the combination of ATM with old and new β-lactamases inhibitors (BLIs) against MBL and ESBL co-producing Gram-negative clinical isolates. Six Enterobacterales and three non-fermenting bacilli co-producing MBL and ESBL determinants were selected as difficult-to-treat pathogens. ESBLs and MBLs genes were characterized by PCR and sequencing. The activity of ATM in combination with seven different BLIs (clavulanate, sulbactam, tazobactam, vaborbactam, avibactam, relebactam, zidebactam) was assessed by microdilution assay and time–kill curve. ATM plus avibactam was the most effective combination, able to restore ATM susceptibility in four out of nine tested isolates, reaching in some cases a 128-fold reduction of the MIC of ATM. In addition, relebactam and zidebactam showed to be effective, but with lesser reduction of the MIC of ATM. E. meningoseptica and C. indologenes were not inhibited by any ATM–BLI combination. ATM–BLI combinations demonstrated to be promising against MBL and ESBL co-producers, hence providing multiple options for treatment of related infections. However, no effective combination was found for some non-fermentative bacilli, suggesting the presence of additional resistance mechanisms that complicate the choice of an active therapy.openMorroni G.; Bressan R.; Fioriti S.; D'Achille G.; Mingoia M.; Cirioni O.; Di Bella S.; Piazza A.; Comandatore F.; Mauri C.; Migliavacca R.; Luzzaro F.; Principe L.; Lagatolla C.Morroni, G.; Bressan, R.; Fioriti, S.; D'Achille, G.; Mingoia, M.; Cirioni, O.; Di Bella, S.; Piazza, A.; Comandatore, F.; Mauri, C.; Migliavacca, R.; Luzzaro, F.; Principe, L.; Lagatolla, C

Effect of ozone oxidative stress on chloride current in human lung cells: Chemical mediators and protective role of catalase

In this work we have investigated the effects of ozone (O3), one of the most noxious pollutants to which respiratory tract is organ most exposed, on Cl currents in human cultured lung epithelial cells (A549 line). Biological and electrophysiological technique was applied to study the action of O3 and its main bio-products (4HNE and H2O2) on Cl currents in A549 cells, which simulates the first barrier encountered by oxidants. O3 exposure (0.1 ppm, 30’) significantly affects Cl current inducing a large outward rectifier component. While 4HNE (up to 25 mM) was not able to reproduce the effect, H2O2 produced by the cell (Glucose Oxidase 10mU) mimicked O3 damage. Then we analyzed the effect of G.O. treatment on ORCC gene expression, the two Cl channels mainly involved in current alteration. RT-PCR showed the ability of oxidative stress due to H2O2 to modulate the gene expression of these channels. Eventually, we verified the protective effect of catalase (1 mM, 1.30 h). The results showed the ability of catalase in suppressing the outward rectifier component activated by O3, bringing back the current values to the control level. This study brings new insights on the mechanisms involved in O3 induced lung tissue damage, confirming its ability to modify the cellular redox homeostasis, and to highlight a new aspect such as the alteration of Cl channel functionality via H2O2 formation