The assessment of green potential of the region development

In the informational society and transformational changes in the economy there is a need in the personalities and ways of making decisions that have the ability to self-development, have an unusual approach and can make a new quality in social and economic life of society. The term "creative" denotes creativity, which "not only put forward the idea, but also brings them to the practical results." In English literature, as a rule, the term «creativity» represent all that is directly related to the creation of something new, the actual process of the creation; product of this process, its subject; the circumstances in which the creative process runs; factors that cause i

The assessment of green potential of the region development

In the informational society and transformational changes in the economy there is a need in the personalities and ways of making decisions that have the ability to self-development, have an unusual approach and can make a new quality in social and economic life of society. The term "creative" denotes creativity, which "not only put forward the idea, but also brings them to the practical results." In English literature, as a rule, the term «creativity» represent all that is directly related to the creation of something new, the actual process of the creation; product of this process, its subject; the circumstances in which the creative process runs; factors that cause i

Mechanistic Insights Into the Anticancer Properties of the Auranofin Analog Au(PEt3)I: A Theoretical and Experimental Study

Au(PEt3)I (AF-I hereafter), the iodide analog of the FDA-approved drug auranofin (AF hereafter), is a promising anticancer agent that produces its pharmacological effects through interaction with non-genomic targets such as the thioredoxin reductase system. AF-I is endowed with a very favorable biochemical profile showing potent in vitro cytotoxic activity against several cancer types including ovarian and colorectal cancer. Remarkably, in a recent publication, some of us reported that AF-I induces an almost complete and rapid remission in an orthotopic in vivo mouse model of ovarian cancer. The cytotoxic potency does not bring about highly severe side effects, making AF-I very well-tolerated even for higher doses, even more so than the pharmacologically active ones. All these promising features led us to expand our studies on the mechanistic aspects underlying the antitumor activity of AF-I. We report here on an integrated experimental and theoretical study on the reactivity of AF-I, in comparison with auranofin, toward relevant aminoacidic residues or their molecular models. Results point out that the replacement of the thiosugar moiety with iodide significantly affects the overall reactivity toward the amino acid residues histidine, cysteine, methionine, and selenocysteine. Altogether, the obtained results contribute to shed light into the enhanced antitumoral activity of AF-I compared with AF

A mixed-valence diruthenium(ii,iii) complex endowed with high stability: from experimental evidence to theoretical interpretation

We herein report the synthesis and multi-technique characterization of [Ru2Cl((2-phenylindol-3-yl)glyoxyl-l-leucine-l-phenylalanine)4], a novel diruthenium(ii,iii) complex obtained by reacting [Ru2(μ-O2CCH3)4Cl] with a dual indolylglyoxylyl dipeptide anticancer agent. We soon realised that the compound is very stable under several different conditions including aqueous buffers or organic solvents. It is also completely unreactive toward proteins. The high stability is also suggested by cellular experiments in a glioblastoma cell line. Indeed, while the parent ligand exerts high cytotoxic effects in the low μM range, the complex is completely non-cytotoxic against the same line, most probably because of the lack of ligand release. To investigate the reasons for such high stability, we carried out DFT calculations that are fully consistent with the experimental findings. The results highlight that the stability of [Ru2Cl((2-phenylindol-3-yl)glyoxyl-l-leucine-l-phenylalanine)4] relies on the nature of the ligand, including its steric hindrance that prevents the reaction of any nucleophilic group with the Ru2 core. Ligand displacement is the key step to allow reactivity with the biological targets of metal-based prodrugs. Accordingly, we discuss the implications of some important aspects that should be considered when active molecules are chosen as ligands for the synthesis of paddle-wheel-like complexes with medicinal applications. This journal i

Mechanistic Evaluations of the Effects of Auranofin Triethylphosphine Replacement with a Trimethylphosphite Moiety

Auranofin, a gold(I)-based complex, is under clinical trials for application as an anticancer agent for the treatment of nonsmall-cell lung cancer and ovarian cancer. In the past years, different derivatives have been developed, modifying gold linear ligands in the search for new gold complexes endowed with a better pharmacological profile. Recently, a panel of four gold(I) complexes, inspired by the clinically established compound auranofin, was reported by our research group. As described, all compounds possess an [Au{P(OMe)3}]+ cationic moiety, in which the triethylphosphine of the parent compound auranofin was replaced with an oxygen-rich trimethylphosphite ligand. The gold(I) linear coordination geometry was complemented by Cl-, Br-, I-, and the auranofin-like thioglucose tetraacetate ligand. As previously reported, despite their close similarity to auranofin, the panel compounds exhibited some peculiar and distinctive features, such as lower log P values which can induce relevant differences in the overall pharmacokinetic profiles. To get better insight into the P-Au strength and stability, an extensive study was carried out for relevant biological models, including three different vasopressin peptide analogues and cysteine, using 31P NMR and LC-ESI-MS. A DFT computational study was also carried out for a better understanding of the theoretical fundamentals of the disclosed differences with regard to triethylphosphine parent compounds

Atomic scale interfacial magnetism and origin of metal-insulator transition in (LaNiO 3_3 3 ) n_n n /(CaMnO 3_3 3 ) m_m m superlattices: a first principles study

Abstract Interfacial magnetism and metal-insulator transition at LaNiO $$_3$$ 3 -based oxide interfaces have triggered intense research efforts, because of the possible implications in future heterostructure device design and engineering. Experimental observation lack in some points a support from an atomistic view. In an effort to fill such gap, we hereby investigate the structural, electronic, and magnetic properties of (LaNiO $$_3$$ 3 ) $$_n$$ n /(CaMnO $$_3$$ 3 ) $$_m$$ m superlattices with varying LaNiO $$_3$$ 3 thickness (n) using density functional theory including a Hubbard-type effective on-site Coulomb term. We successfully capture and explain the metal-insulator transition and interfacial magnetic properties, such as magnetic alignments and induced Ni magnetic moments which were recently observed experimentally in nickelate-based heterostructures. In the superlattices modeled in our study, an insulating state is found for n=1 and a metallic character for n=2, 4, with major contribution from Ni and Mn 3d states. The insulating character originates from the disorder effect induced by sudden environment change for the octahedra at the interface, and associated to localized electronic states; on the other hand, for larger n, less localized interfacial states and increased polarity of the LaNiO $$_3$$ 3 layers contribute to metallicity. We discuss how the interplay between double and super-exchange interaction via complex structural and charge redistributions results in interfacial magnetism. While (LaNiO $$_3$$ 3 ) $$_n$$ n /(CaMnO $$_3$$ 3 ) $$_m$$ m superlattices are chosen as prototype and for their experimental feasibility, our approach is generally applicable to understand the intricate roles of interfacial states and exchange mechanism between magnetic ions towards the overall response of a magnetic interface or superlattice

Reactivity of antitumor coinage metal-based N-heterocyclic carbene complexes with cysteine and selenocysteine protein sites

The reaction of the antitumor M(I)-bis-N-heterocyclic carbene (M(I)-NHC) complexes, M = Cu, Ag, and Au, with their potential protein binding sites, i.e. cysteine and selenocysteine, was investigated by means of density functional theory approaches. Capped cysteine and selenocysteine were employed to better model the corresponding residues environment within peptide structures. By assuming the neutral or deprotonated form of the side chains of these amino acids and by considering the possible assistance of an external proton donor such as an adjacent acidic residue or the acidic component of the surrounding buffer environment, we devised five possible routes leading to the binding of the investigated M(I)-NHC scaffolds to these protein sites, reflecting their different location in the protein structure and exposure to the bulk. The targeting of either cysteine or selenocysteine in their neutral forms is a kinetically unfavored process, expected to be quite slow if observable at all at physiological temperature. On the other hand, the reaction with the deprotonated forms is much more favored, even though an external proton source is required to assist the protonation of the leaving carbene. Our calculations also show that all coinage metals are characterized by a similar reactivity toward the binding of cysteine and selenocysteine sites, although the Au(I) complex has significantly higher reaction and activation free energies compared to Cu(I) and Ag(I)

In vitro anti-sars-cov-2 activity of selected metal compounds and potential molecular basis for their actions based on computational study

Metal-based drugs represent a rich source of chemical substances of potential interest for the treatment of COVID-19. To this end, we have developed a small but representative panel of nine metal compounds, including both synthesized and commercially available complexes, suitable for medical application and tested them in vitro against the SARS-CoV-2 virus. The screening revealed that three compounds from the panel, i.e., the organogold(III) compound Aubipyc, the ruthenium(III) complex KP1019, and antimony trichloride (SbCl3 ), are endowed with notable antiviral properties and an acceptable cytotoxicity profile. These initial findings prompted us to perform a computational study to unveil the likely molecular basis of their antiviral actions. Calculations evidenced that the metalation of nucleophile sites in SARS-CoV-2 proteins or nucleobase strands, induced by Aubipyc, SbCl3, and KP1019, is likely to occur. Remarkably, we found that only the deprotonated forms of Cys and Sec residues can react favorably with these metallodrugs. The mechanistic implications of these findings are discussed

Reactions of Arsenoplatin-1 with Protein Targets: A Combined Experimental and Theoretical Study

Arsenoplatin-1 (AP-1) is a dual-action anticancer metallodrug with a promising pharmacological profile that features the simultaneous presence of a cisplatin-like center and an arsenite center. We investigated its interactions with proteins through a joint experimental and theoretical approach. The reactivity of AP-1 with a variety of proteins, including carbonic anhydrase (CA), superoxide dismutase (SOD), myoglobin (Mb), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and human serum albumin (HSA), was analyzed by means of electrospray ionization mass spectrometry (ESI MS) measurements. In accordance with previous observations, ESI MS experiments revealed that the obtained metallodrug-protein adducts originated from the binding of the [(AP-1)-Cl]+ fragment to accessible protein residues. Remarkably, in two cases, i.e., Mb and GAPDH, the formation of a bound metallic fragment that lacked the arsenic center was highlighted. The reactions of AP-1 with various nucleophiles side chains of neutral histidine, methionine, cysteine, and selenocysteine, in neutral form as well as cysteine and selenocysteine in anionic form, were subsequently analyzed through a computational approach. We found that the aquation of AP-1 is energetically disfavored, with a reaction free energy of +19.2 kcal/mol demonstrating that AP-1 presumably attacks its biological targets through the exchange of the chloride ligand. The theoretical analysis of thermodynamics and kinetics for the ligand-exchange processes of AP-1 with His, Met, Cys, Sec, Cys-, and Sec- side chain models unveils that only neutral histidine and deprotonated cysteine and selenocysteine are able to effectively replace the chloride ligand in AP-1

Anti-Staphylococcal Activity of the Auranofin Analogue Bearing Acetylcysteine in Place of the Thiosugar: An Experimental and Theoretical Investigation

Auranofin (AF, hereafter) is an orally administered chrysotherapeutic agent approved for the treatment of rheumatoid arthritis that is being repurposed for various indications including bacterial infections. Its likely mode of action involves the impairment of the TrxR system through the binding of the pharmacophoric cation [AuPEt3 ]+. Accordingly, a reliable strategy to expand the medicinal profile of AF is the replacement of the thiosugar moiety with different ligands. Herein, we aimed to prepare the AF analogue bearing the acetylcysteine ligand (AF-AcCys, hereafter) and characterize its anti-staphylococcal activity. Biological studies revealed that AF-AcCys retains an antibacterial effect superimposable with that of AF against Staphylococcus aureus, whereas it is about 20 times less effective against Staphylococcus epidermidis. Bioinorganic studies confirmed that upon incubation with human serum albumin, AF-AcCys, similarly to AF, induced protein metalation through the [AuPEt3 ]+ fragment. Additionally, AF-AcCys appeared capable of binding the dode-capeptide Ac-SGGDILQSGCUG-NH2, corresponding to the tryptic C-terminal fragment (488–499) of hTrxR. To shed light on the pharmacological differences between AF and AF-AcCys, we carried out a comparative experimental stability study and a theoretical estimation of bond dissociation energies, unveiling the higher strength of the Au–S bond in AF-AcCys. From the results, it emerged that the lower lipophilicity of AF-AcCys with respect to AF could be a key feature for its different antibacterial activity. The differences and similarities between AF and AF-AcCys are discussed, alongside the opportunities and consequences that chemical structure modifications imply