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A dicarboxylato-diamide-type compound 2,2'-[(1,2-dioxoethane-1,2- -diyl)diimino]dibenzoic acid (H4obbz) (1) was synthesized and characterized. The crystal structure of K2H2obbz?2H2O (2) was determined by X-ray diffracttion analysis. The cytotoxic activities of the compounds were tested against four different cancer cell lines MCF-7, A549, HT-29, HeLa and a human normal cell line MRC-5. The results indicate reasonable dose-dependent cytotoxicity of the ligands that show selectivity against the tested carcinoma and healthy cell lines. Flow cytometric analysis and fluorescence microscopy showed that the most active compound, H4obbz, induced apoptosis and G0/G1 cell cycle arrest, indicating blockage of DNA synthesis as a possible mechanism that triggers apoptosis. Docking and molecular dynamics simulations gave similar responses regarding interactions (binding) between their ligands and chaperon Grp78. The MMGBSA determined ?G binding energies were in the range from ?104 to ?140 kJ mol-1.

Here, we report a mild approach to the construction of the difluoroalkyl bicyclopentane and bicycloheptane (CF2-BCP and CF2-BCHep) units, as the structural surrogates of para- and meta-substituted aryl ketones and aryl ethers. The chemistry is orchestrated by the key activity of a dihydrobenzoacridine photocatalyst (PC). Depending by the nature of the substrate, the PC engages in catalytic electron-donor acceptor (EDA) complex or promotes the direct reduction of the substrate (Ered up to -1.9 V vs SCE) through a single-electron transfer (SET) mechanism. These two convergent manifolds leads to the generation of the reactive R-CF2 radical that reacts trough a strain-release atom-transfer-radical addition (ATRA) process with the [1.1.1]- or [3.1.1]-propellane. The method is general and tolerant of a variety of functional groups, such as sulfones, amines, amides or alkynes (30 examples, yields up to 90%), and extendable to complex bioactive molecules, including aminoacids, dipeptides or carbohydrates. The structural features of the CF2-BCP hybrid bioisostere were investigated in the solid state by single crystal X-ray analysis. Finally, we synthesised a CF2-BCP analogue of a Leukotriene A4 (LTA4) hydrolase inhibitor, replacing the original aryl ether motif. Interestingly, in-silico docking studies indicated that this new molecule maintains the same arrangement and key interactions within the enzyme pocket.

We report the synthesis and characterization of three half-sandwich Ru(II) arene complexes [(η6-arene)Ru(N,N′)L][PF6]2 containing arene = p-cymene, N,N′ = bipyridine, and L = pyridine meta- with methylenenaphthalimide (C1), methylene(nitro)naphthalimide (C2), or methylene(piperidinyl)naphthalimide (C3). The naphthalimide acts as an antenna for photoactivation. After 3 h of irradiation with blue light, the monodentate pyridyl ligand had almost completely dissociated from complex C3, which contains an electron donor on the naphthalimide ring, whereas only 50% dissociation was observed for C1 and C2. This correlates with the lower wavelength and strong absorption of C3 in this region of the spectrum (λmax = 418 nm) compared with C1 and C2 (λmax = 324 and 323 nm, respectively). All the complexes were relatively non-toxic towards A549 human lung cancer cells in the dark, but only complex C3 exhibited good photocytoxicity towards these cancer cells upon irradiation with blue light (IC50 = 10.55 ± 0.30 μM). Complex C3 has the potential for use in photoactivated chemotherapy (PACT).

Many bacterial strains are developing mechanism of resistance to antibiotics, rendering last-resort antibiotics inactive. Therefore, new drugs are needed and in particular metal-based compounds represent a valid starting point to explore new antibiotic classes. In this study, we have chosen to investigate gallium(III) complexes for their potential antimicrobial activity against different strains of Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa which have developed different type of resistance mechanism, including the expression of β-lactamases (NDM-1, ESβL, or AmpC) or the production of biofilm. We studied a series of thiosemicarbabazones derived from pyridoxal, their related Ga(III) complexes, and the speciation in solution of the Ga(III)/ligand systems as a function of the pH. Proton dissociation constants and conditional stability constants of Ga(III) complexes were evaluated by UV/Vis spectroscopy, and the most relevant species at physiological pH were identified. The compounds are active against resistant Gram-negative strain with minimal inhibitory concentration in the μM range, while no cytotoxicity was detected in eukaryotic cells.

Twelve naphthochromenone photocatalysts (PCs) were synthesized on gram scale. They absorb across the UV/Vis range and feature an extremely wide redox window (up to 3.22 eV) that is accessible using simple visible light irradiation sources (CFL or LED). Their excited-state redox potentials, PC*/PC.- (up to 1.65 V) and PC.+ /PC* (up to -1.77 V vs. SCE), are such that these novel PCs can engage in both oxidative and reductive quenching mechanisms with strong thermodynamic requirements. The potential of these bimodal PCs was benchmarked in synthetically relevant photocatalytic processes with extreme thermodynamic requirements. Their ability to efficiently catalyze mechanistically opposite oxidative/reductive photoreactions is a unique feature of these organic photocatalysts, thus representing a decisive advance towards generality, sustainability, and cost efficiency in photocatalysis.

Resistant bacteria represent an urgent worldwide threat. NDM-1-producing strains are rendering the last line antibiotics less effective. Six bismuth complexes of general formula BiLCl

A variety of highly functionalised N-containing polycycles (35 examples) are synthesised from simple indoles and aromatic ketones through a mild visible-light Paternò–Büchi process. Tetrahydrooxeto[2,3-b]indole scaffolds, with up to three contiguous all-substituted stereocenters, are generated in high yield (up to >98%) and excellent site- regio- and diastereocontrol (>20 : 1). The use of visible light (405 or 465 nm) ensures enhanced performances by switching off undesired photodimerisation side reactions. The reaction can be easily implemented using a microfluidic photoreactor with improved productivity (up to 0.176 mmol h−1) and generality. Mechanistic investigations revealed that two alternative reaction mechanisms can account for the excellent regio- and diastereocontrol observed., A scalable visible-light [2 + 2]-heterocycloaddition process allows the dearomatisation of indoles to complex biorelevant polycycles.

Dysregulated levels of microRNAs (miRNAs or miRs), involved in oncogenic pathways, have been proposed to contribute to the aggressiveness of malignant pleural mesothelioma (MPM). Previous studies have highlighted the downregulation of miRNA miR-486-5p in patients with mesothelioma and the introduction of miRNA mimics to restore their reduced or absent functionality in cancer cells is considered an important therapeutic strategy. The aim of the present study was to evaluate the mechanisms through which miRNAs may influence the functions, proliferation and sensitivity to cisplatin of MPM cells. In the present study, a miR-486-5p mimic was transfected into the H2052 and H28 MPM cell lines, and cell viability, proliferation, apoptosis and mitochondrial membrane potential were monitored. miR-486-5p overexpression led to a clear impairment of cell proliferation, targeting CDK4 and attenuating cell cycle progression. In addition, transfection with miR-486-5p mimic negatively regulated the release of inflammatory factors and the expression of Provirus integration site for Moloney murine leukaemia virus 1 (PIM1). The sensitivity of the cells to cisplatin was enhanced by enhancing the apoptotic effects of the drug and impairing mitochondrial function. On the whole, the present study demonstrates that miR-486-5p may play an important role in MPM treatment by targeting multiple pathways involved in tumour development and progression. These activities may be mostly related to the downregulation of PIM1, a crucial regulator of cell survival and proliferation. Furthermore, these results provide support for the combined use of miR-486-5p with chemotherapy as a therapeutic strategy for MPM.

The control of the fungal contamination on crops is considered a priority by the sanitary authorities of an increasing number of countries, and this is also due to the fact that the geographic areas interested in mycotoxin outbreaks are widening. Among the different pre- and post-harvest strategies that may be applied to prevent fungal and/or aflatoxin contamination, fungicides still play a prominent role; however, despite of countless efforts, to date the problem of food and feed contamination remains unsolved, since the essential factors that affect aflatoxins production are various and hardly to handle as a whole. In this scenario, the exploitation of bioactive natural sources to obtain new agents presenting novel mechanisms of action may represent a successful strategy to minimize, at the same time, aflatoxin contamination and the use of toxic pesticides. The Aflatox® Project was aimed at the development of new-generation inhibitors of aflatoxigenic Aspergillus spp. proliferation and toxin production, through the modification of naturally occurring molecules: a panel of 177 compounds, belonging to the thiosemicarbazones class, have been synthesized and screened for their antifungal and anti-aflatoxigenic potential. The most effective compounds, selected as the best candidates as aflatoxin containment agents, were also evaluated in terms of cytotoxicity, genotoxicity and epi-genotoxicity to exclude potential harmful effect on the human health, the plants on which fungi grow and the whole ecosystem.

The control of the fungal contamination on crops is considered a priority by the sanitary authorities of an increasing number of countries, and this is also due to the fact that the geographic areas interested in mycotoxin outbreaks are widening. Among the different pre- and post-harvest strategies that may be applied to prevent fungal and/or aflatoxin contamination, fungicides still play a prominent role, however, despite of countless efforts, to date the problem of food and feed contamination remains unsolved, since the essential factors that affect aflatoxins production are various and hardly to handle as a whole. In this scenario, the exploitation of bioactive natural sources to obtain new agents presenting novel mechanisms of action may represent a successful strategy to minimize, at the same time, aflatoxin contamination and the use of toxic pesticides. The Aflatox® Project was aimed at the development of new-generation inhibitors of aflatoxigenic Aspergillus spp. proliferation and toxin production, through the modification of naturally occurring molecules: a panel of 177 compounds, belonging to the thiosemicarbazones class, have been synthesized and screened for their antifungal and anti-aflatoxigenic potential. The most effective compounds, selected as the best candidates as aflatoxin containment agents, were also evaluated in terms of cytotoxicity, genotoxicity and epi-genotoxicity to exclude potential harmful effect on the human health, the plants on which fungi grow and the whole ecosystem.

The synthesis, photoactivation and biological activity of a new piano-stool Ru(II) complex is herein reported. The peculiarity of this complex is that its monodentate ligand which undergoes the photodissociation is an asymmetric bis-thiocarbohydrazone ligand that possesses a pyridine moiety binding to Ru(II) and the other moiety contains a quinoline that endows the ligand with the capacity of chelating other metal ions. In this way, upon dissociation, the ligand can be released in the form of a metal complex. In this article, the double ability of this new Ru(II) complex to photorelease the ligand and to chelate copper and nickel is explored and confirmed. The biological activity of this compound is studied in cell line A549 revealing that, after irradiation, proliferation inhibition is reached at very low half maximal inhibitory concentration (IC50) values. Further, biological assays reveal that the dinuclear complex containing Ni is internalized in cells.

Great are the expectations for a new generation of antimicrobials, and strenuous are the research efforts towards the exploration of diverse molecular scaffolds—possibly of natural origin – aimed at the synthesis of new compounds against the spread of hazardous fungi. Also high but winding are the paths leading to the definition of biological targets specifically fitting the drug’s structural characteristics. The present study is addressed to inspect differential biological behaviours of cinnamaldehyde and benzaldehyde thiosemicarbazone scaffolds, exploiting the secondary metabolism of the mycotoxigenic phytopathogen Aspergillus flavus. Interestingly, owing to modifications on the parent chemical scaffold, some thiosemicarbazones displayed an increased specificity against one or more developmental processes (conidia germination, aflatoxin biosynthesis, sclerotia production) of A. flavus biology. Through the comparative analysis of results, the ligand-based screening strategy here described has allowed us to delineate which modifications are more promising for distinct purposes: from the control of mycotoxins contamination in food and feed commodities, to the environmental management of microbial pathogens, to the investigation of specific structure–activity features for new generation drug discovery.

Thiosemicarbazones (TSC) and their metal complexes display diverse biological activities and are active against multiple pathological conditions ranging from microbial infections to abnormal cell proliferation. Ribonucleotide reductase (RNR) is considered one of the main targets of TSCs, yet, the existence of additional targets, differently responsible for the multifaceted activities of TSCs and their metal complexes has been proposed. To set the basis for a more comprehensive delineation of their mode of action, we chemogenomically profiled the cellular effects of bis(citronellalthiosemicarbazonato)nickel(II) [Ni(S-tcitr)2] using the unicellular eukaryote Saccharomyces cerevisiae as a model organism. Two complementary genomic phenotyping screens led to the identification of 269 sensitive and 56 tolerant deletion mutant strains and of 14 genes that when overexpressed make yeast cells resistant to an otherwise lethal concentration of Ni(S-tcitr)2. Chromatin remodeling, cytoskeleton organization, mitochondrial function and iron metabolism were identified as lead cellular processes responsible for Ni(S-tcitr)2 toxicity. The latter process, and particularly glutaredoxin-mediated iron loading of RNR, was found to be affected by Ni(S-tcitr)2. Given the multiple pathways regulated by glutaredoxins, targeting of these proteins by Ni(S-tcitr)2 can negatively affect various core cellular processes that may critically contribute to Ni(S-tcitr)2 cytotoxicity.

Background: In recent decades, there has been an increase in male infertility, and in many cases, the etiology remains unclear. Several studies relate male hypo-fertility to xenobiotic exposure, even if no data exist about multiple exposure at the environmental level. Methods: The study involved 86 males with diagnosis of idiopathic male infertility (IMI), and 46 controls with no alteration in sperm characteristics. Seminal plasma (SP) and urine samples were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) to quantify biomarkers of exposure (the main metabolites of benzene, toluene, 1,3-butadiene, 3-monochloropropanediol, styrene, and naphthol) and effect (oxidized products of nucleic acids).Results: Biomarker concentrations were similar in subjects with IMI and controls even if a stronger correlation between biomarkers of exposure and effects were observed in SP. Data show that, both in SP and urine, most metabolites were inter-correlated, indicating a simultaneous co-exposure to the selected substances at the environmental level. Principal component analysis showed in SP the clustering of mercapturic acids indicating a preferential metabolic pathway with Glutathione (GSH) depletion and, consequently, an increase of oxidative stress. This result was also confirmed by multivariable analysis through the development of explanatory models for oxidized products of nucleic acids. Conclusions: This study highlights how oxidative stress on the male reproductive tract can be associated with a different representation of metabolic pathways making the reproductive tract itself a target organ for different environmental pollutants. Our results demonstrate that SP is a suitable matrix to assess the exposure and evaluate the effects of reproductive toxicants in environmental/occupational medicine. The statistical approach proposed in this work represents a model appropriate to study the relationship between multiple exposure and effect, applicable even to a wider variety of chemicals.

A large variety of highly functionalized N-containing polycycles (35 examples) are synthetized from simple indoles and aromatic ketones through a mild visible-light-driven [2+2]-heterocycloaddition process. Tetrahydrooxeto[2,3b]indole scaffolds, with up to three contiguous all-substituted stereo-centers are generated in high yield (up to >98%) and excellent site- regio- and diastereocontrol (>20:1). The use of visible light (405 or 465 nm) ensures enhanced performances by switching off undesired photodimerization reactions. Mechanistic investigations revealed that the operative reaction mechanism is dependent by the nature of the used ketone-substrate.

The discovery of chemical methods enabling the construction of carbocycle-fused uracils which embody a three-dimensional and functional-group-rich architecture is a useful tool in medicinal chemistry oriented synthesis. In this work, an unprecedented amine-catalyzed [4+2] cross-cycloaddition is documented; it involves remotely enolizable 6-methyluracil-5-carbaldehydes and β-aryl enals, and chemoselectively produces two novel bicyclic and tricyclic fused uracil chemotypes in good yields with a maximum level of enantiocontrol. In-depth mechanistic investigations and control experiments support an intriguing homo-synergistic organocatalytic approach, where the same amine organocatalyst concomitantly engages both aldehyde partners in a stepwise eliminative [4+2] cycloaddition, whose vinylogous iminium ion intermediate product may diverge-depending upon conditions-to either bicyclic targets by hydrolysis or tricyclic products by a second homo-synergistic trienamine-mediated stepwise [4+2] cycloaddition.

Seasonal influenza A and B viruses represent a global concern. Antiviral drugs are crucial to treat severe influenza in high-risk patients and prevent virus spread in case of a pandemic. The emergence of viruses showing drug resistance, in particular for the recently licensed polymerase inhibitor baloxavir marboxil, drives the need for developing alternative antivirals. The endonuclease activity residing in the N-terminal domain of the polymerase acidic protein (PAN) is crucial for viral RNA synthesis and a validated target for drug design. Its function can be impaired by molecules bearing a metal-binding pharmacophore (MBP) able to coordinate the two divalent metal ions in the active site. In the present work, the 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one scaffold is explored for the inhibition of influenza virus PA endonuclease. The structure-activity relationship was analysed by modifying the substituents on the lipophilic moiety linked to the MBP. The new compounds exhibited nanomolar inhibitory activity in a FRET-based enzymatic assay, and a few compounds (15-17, 21) offered inhibition in the micromolar range, in a cell-based influenza virus polymerase assay. When investigated against a panel of PA-mutant forms, compound 17 was shown to retain full activity against the baloxavir-resistant I38T mutant. This was corroborated by docking studies providing insight into the binding mode of this novel class of PA inhibitors. ispartof: BIOORGANIC CHEMISTRY vol:116 ispartof: location:United States status: published

The possibility to influence the physiological concentration of copper ions through the careful choice of ligands is emerging as a novel intriguing strategy in the treatment of pathologies such as cancer and Alzheimer. Thiosemicarbazones play an important role in this field, because they offer a wide variety of potential functionalizations and different kinds of coordination modes. Here we report the synthesis of some 8-hydroxyquinoline thiosemicarbazone ligands containing an ONN'S donor set and their Zn(II) and Cu(II) complexes. The metal complexes were characterized in solution and in the solid state and the X-ray structure of one of the copper(II) complex is reported. The Cu(II) complexes were characterized also by means of quantum mechanical calculations. The Cu(II) complexes displayed cytostatic activity in different cancer cell models. In particular, the most active Cu(II) complex significantly inhibited cell proliferation with an IC50 value lower than 1 μM; this effect was associated with a block of the cell cycle in the G2/M phase. This Cu(II) complex induced neither the production of reactive oxygen species (ROS) nor the accumulation of p53 protein, suggesting the lack of DNA damage.

Nanoparticles are widely studied for applications in medical science. In recent years, they have been developed for agronomical purposes to target microbial pest such as bacteria, fungi, and viruses. Nanoparticles are also proposed to limit the use of pesticides, whose abuse is causing environmental impact and human health concerns. In this study, nanoparticles were obtained by using poly-(e-caprolactone), a polyester chosen for its biocompatibility and biodegradability properties. Poly-(e-caprolactone) nanoparticles were formulated by using poly(vinyl alcohol) or Pluronic® F127 as non-ionic surfactants, and then loaded with benzophenone or valerophenone thiosemicarbazone, two compounds that inhibit aflatoxin production by Aspergillus flavus. The different types of nanoparticles were compared in terms of size, polydispersity index, morphology, and drug loading capacity. Finally, their effects were investigated on growth, development, and aflatoxin production in the aflatoxigenic species Aspergillus flavus, a ubiquitous contaminant of maize, cereal crops, and derived commodities. Aflatoxin production was inhibited to various extents, but the best inhibitory effect was obtained with respect to sclerotia production that was most effectively suppressed by both benzophenone and valerophenone thiosemicarbazone-loaded nanoparticles. These data support the idea that it is possible to use such nanoparticles as an alternate to pesticides for the control of mycotoxigenic sclerotia-forming fungi.

Metal complexes still represent promising pharmacological tools in the development of new anticancer drugs. Bis(citronellalthiosemicarbazonate)nickel(ii) is a metal compound extremely effective against leukemic and NCS cancer cell lines. Preliminary experiments performed with this compound and with its Cu(ii) and Pt(ii) analogues evidenced alterations, detectable by comet assay, in the DNA of treated U937 cells. In addition, [Cu(tcitr)2] and [Pt(tcitr)2] were also able to induce gene mutations and produce frameshift events. To gain further insights into the mechanism of action of these metal compounds, we carried out a multidisciplinary study to investigate whether their biological activity can be ascribed to the direct interaction with DNA or with chromatin. The DNA interaction was investigated by means of CD and UV-Vis spectroscopic techniques and by AFM, whereas the chromatin interaction was studied by analyzing the effects of the compounds on the structure of a peptide that mimicks the potential metal binding site in the “C-tail” region of histone H2A by means of NMR, CD, UV-Vis and MS. The intensities of the effects induced by the metal compounds on the peptide follow the order [Ni(tcitr)2] > [Pt(tcitr)2] ≫ [Cu(tcitr)2]. From the AFM data, a remarkable DNA compaction was observed in the presence of [Pt(tcitr)2], while [Ni(tcitr)2] causes the formation of large interlaced DNA aggregates.

Aflatoxins are secondary fungal metabolites that can contaminate feed and food. They are a cause of growing concern worldwide, because they are potent carcinogenic agents. Thiosemicarbazones are molecules that possess interesting antiaflatoxigenic properties, but in order to use them as crop-protective agents, their cytotoxic and genotoxic profiles must first be assessed. In this paper, a group of thiosemicarbazones and a copper complex are reported as compounds able to antagonize aflatoxin biosynthesis, fungal growth, and sclerotia biogenesis in Aspergillus flavus. The two most interesting thiosemicarbazones found were noncytotoxic on several cell lines (CRL1790, Hs27, HFL1, and U937), and therefore, they were submitted to additional analysis of mutagenicity and genotoxicity on bacteria, plants, and human cells. No mutagenic activity was observed in bacteria, whereas genotoxic activity was revealed by the Alkaline Comet Assay on U937 cells and by the test of chromosomal aberrations in Allium cepa.

The development of microbial antibiotic resistance has become one of the biggest threats to global health and the search for new molecules active against resistant pathogenic strains is a challenge that must be tackled. In many cases nosocomial infections are caused by bacteria characterized by multi-drug resistance patterns and by their ability to produce biofilms. These properties lead to the persistence of pathogens in the hospital environment. This paper reports the synthesis and characterization of three thiosemicarbazone derivatives based on a compound containing the cinnamaldehyde natural scaffold but possessing different logPow values. These molecules are then used as ligands to prepare complexes of the Cu(II) and Zn(II) ions. All these compounds, ligands and complexes, were screened in vitro on stains of Escherichia coli and Klebsiella pneumoniae for their antibacterial activity. Despite their molecular similarity they revealed variegated behaviors. Only two of them present interesting antimicrobial properties and have also been studied to verify their stability in solution. The compound with the lowest partition coefficient is the most promising. The minimal bactericidal concentration on K. pneumoniae and E. coli of these substances are very interesting and demonstrate that the use of metalloantibiotics is a promising device to fight antibiotic resistance.

The prognosis of patients affected by malignant pleural mesothelioma (MPM) is presently poor and no therapeutic strategies have improved their survival yet. Introduction of miRNA mimics to restore their reduced or absent functionality in cancer cells is considered an important opportunity and a combination of miR's might be even more effective. In the present study, miR-16 and miR-34a were transfected, singularly and in combination, in MPM cell lines H2052 and H28, and their effects on cell proliferation and sensitivity to cisplatin are reported. Interestingly, the overexpression of both miRs, alone or combined, slows down the cell cycle progression, modulates the p53 and HMGB1 expression and increases the sensitivity of cells to cisplatin, producing a marked impairment of cell proliferation and strengthening the apoptotic effect of the drug. However, the co-overexpression of the two miRs results more effective only in the regulation of the cell cycle, but does not enhance the sensitivity of MPM cells to cisplatin. Consequently, although the potential of miR-16 and miR-34a is confirmed, we must conclude that their combination does not improve the response of MPM to chemotherapy.

A comparative study between two bisthiosemicarbazones, 2,3-butanedione bis(4,4-dimethyl-3-thiosemicarbazone) and 2,3-butanedione bis(2-methyl-3-thiosemicarbazone), and their copper(ii) complexes is reported. The four compounds have been tested on a leukemia cell line U937 (p53-null) and on an adenocarcinoma cell line A549. The study includes cell viability, cell cycle, morphological changes, assessment of apoptosis, analysis of autophagy, measurement of reactive oxygen species (ROS) and of lipid peroxidation, protein determination, assessment of the expression of p53 and cellular uptake of metal complexes. Tests about the copper uptake under normoxic and hypoxic conditions were also carried out on a solid tumour cell line A549. The four compounds under study elicit different effects on the two lines adopted as representatives of p53 and p53-null cells. The role of the metal is relevant and it is likely that the metal-mediated oxidative stress plays an essential role in the whole process. The mechanisms induced by these molecules differ not only as a function of the cell line but also of dose. The responses include two distinct self-destructive processes, autophagy and apoptosis.

We report studies of a novel series of Pt(IV) complexes exhibiting an asymmetric combination of acetylamido and carboxylato ligands in the axial positions. We demonstrate efficient synthesis of a series of analogues, differing in the alkyl chain length and hence lipophilicity, from a stable acetylamido/hydroxido complex formed by reaction of cisplatin with peroxyacetimidic acid (PAIA). NMR spectroscopy and X-ray crystallography confirm the identity of the resulting complexes, and highlight subtle differences in the structure and stability of acetylamido complexes compared to the equivalent acetato complexes. Reduction of acetylamido complexes, whether achieved chemically or electro-chemically, is significantly more difficult than that of acetate complexes, resulting in lower antiproliferative activity for shorter-chain complexes. For those with longer chains and hence greater cell uptake, this difference is negated and acetylamido complexes are as active as acetato analogues, both exhibiting antiproliferative potency (1/IC50) against A2780 ovarian cancer cells similar to that of cisplatin.

As key players in biotic stress response of plants, jasmonic acid (JA) and its derivatives cover a specific and prominent role in pathogens-mediated signaling and hence are promising candidates for a sustainable management of phytopathogenic fungi. Recently, JA directed antimicrobial effects on plant pathogens has been suggested, supporting the theory of oxylipins as double gamers in plant-pathogen interaction. Based on these premises, six derivatives (dihydrojasmone and cis-jasmone, two thiosemicarbazonic derivatives and their corresponding complexes with copper) have been evaluated against 13 fungal species affecting various economically important herbaceous and woody crops, such as cereals, grapes and horticultural crops: Phaeoacremonium minimum, Neofusicoccum parvum, Phaeomoniella chlamydospora, Fomitiporia mediterranea, Fusarium poae, F. culmorum, F. graminearum, F. oxysporum f. sp. lactucae,F. sporotrichioides, Aspergillus flavus, Rhizoctonia solani,Sclerotinia spp. and Verticillium dahliae. The biological activity of these compounds was assessed in terms of growth inhibition and, for the two mycotoxigenic species A. flavus and F. sporotrichioides, also in terms of toxin containment. As expected, the inhibitory effect of molecules greatly varied amongst both genera and species, cis-jasmone thiosemicarbazone in particular has shown the wider range of effectiveness. However, our results show that thiosemicarbazones derivatives are more effective than the parent ketones in limiting fungal growth and mycotoxins production, supporting possible applications for the control of pathogenic fungi.

Certain metal complexes can have a great antitumor activity, as the use of cisplatin in therapy has been demonstrating for the past fifty years. Copper complexes, in particular, have attracted much attention as an example of anticancer compounds based on an endogenous metal. In this paper we present the synthesis and the activity of a series of copper(II) complexes with variously substituted salicylaldehyde thiosemicarbazone ligands. The in vitro activity of both ligands and copper complexes was assessed on a panel of cell lines (HCT-15, LoVo and LoVo oxaliplatin resistant colon carcinoma, A375 melanoma, BxPC3 and PSN1 pancreatic adenocarcinoma, BCPAP thyroid carcinoma, 2008 ovarian carcinoma, HEK293 non-transformed embryonic kidney), highlighting remarkable activity of the metal complexes, in some cases in the low nanomolar range. The copper(II) complexes were also screened, with good results, against 3D spheroids of colon (HCT-15) and pancreatic (PSN1) cancer cells. Detailed investigations on the mechanism of action of the copper(II) complexes are also reported: they are able to potently inhibit Protein Disulfide Isomerase, a copper-binding protein, that is recently emerging as a new therapeutic target for cancer treatment. Good preliminary results obtained in C57BL mice indicate that this series of metal-based compounds could be a very promising weapon in the fight against cancer.

The wide range of applications of nanoparticles (NPs) has increased the probability of environmental and occupational exposure. In a previous comparative study on cell line A549, we observed that oxidative stress caused by Co3O4 NPs affects the energetic homeostasis and the detoxification capacity, preventing autophagy induced by TiO2 NPs. In this study, we have investigated the effects of NPs on the cell cycle.Cytofluorimetric analysis showed a slow-down of the cell cycle progression for both NPs, with increases in the percentage of resting cells in the G0/G1. These observations were confirmed by a reduced expression of all cyclins, especially of CCNE1 and CDK2, involved in the late stages of the G1 phase, coupled with a significant increase in the expression of p21 only for Co3O4 NP exposure. On the contrary, the effects of TiO2 NPs were modest. Cell cycle related miRNA-34a, miRNA-126 and miRNA-1290 resulted increased at different early time-points (4-8h) but were down-expressed at 24h-48h only after TiO2 NP exposure. Our results show that NPs have an antiproliferative effect and deregulate cell cycle on A549 cells. These effects should not be underestimated because regulation of cycle progression is crucial for cell survival and repair of genetic damage.

We introduce 3-(alkoxycarbonyl-2-alkyliden)-2-oxindoles as pronucleophilic donors in the direct, vinylogous Michael addition to nitroolefins orchestrated by a chiral, bifunctional cinchona-thiourea organocatalyst. This reaction displays excellent levels of γ-site-, diastereo- and enantioselectivity delivering valuable enantioenriched functionalized oxindoles. Of note, the C-γ enolization of these pronucleophiles by the organocatalyst generates a multidentate, captodative dienolate that delivers vinylogous adducts with an unprecedented Z-selectivity through a peculiar interaction with the catalyst and the nitroolefin. The optimized procedure is operatively simple: the reaction is conducted in air, at room temperature, with low catalyst loading (up to 1 mol%). The synthetic versatility of these Michael adducts is demonstrated by several transformations leading to a valuable quaternary oxindolyl proline analogue and a chiral spirocyclic furoindolone structure. Finally, a mechanistic rationale and a suitable transition state accounting for the observed selectivities are proposed, which are supported by DFT calculations. (Figure presented.).

The asymmetric synthesis of a set of hydroxyphenyl γ-valerolactones was achieved starting from 2-silyloxyfuran and alkoxy-substituted benzaldehydes as common precursors. Key synthesis steps included an enantioselective vinylogous Mukaiyama aldol reaction and a Barton–McCombie deoxygenation. Five enantioenriched γ-valerolactone targets were obtained in 5–6 steps, 18–63% overall yields and 82–98 % ee, paving the way for the straightforward entry to this class of biologically effective and poorly available flavan-3-ol metabolites. In parallel, an unprecedented one-pot reductive ring expansion process was fortuitously discovered, yielding racemic δ-lactone analogues from phenolic butanolide precursors.

In this paper, we report the syntheses, characterization and studies on the inhibition efficiency in mild steel acidic corrosion of 4-fluorobenzaldehyde thiosemicarbazone, Hfbt, 4-fluorobenzaldehyde 2-methylthiosemicarbazone, Me-fbt, and their Zn(II) complexes [Zn(fbt)2] and [Zn(Me-fbt)2]Cl2. The ligands present a good degree of activity that can be assigned to their molecular planar shape and to the presence of electron lone pairs that can interact with metal orbitals. The two zinc complexes present diametrically opposite properties: [Zn(fbt)2] is by far less active than the ligands, while [Zn(Me-fbt)2]Cl2 is the most efficient. Quantum chemical studies were carried out in an attempt to rationalize this behaviour.

Two small series of Pt(IV) complexes of the general formula cis,cis,trans-[PtA2Cl2L2] (A = 2 × NH3, series 1, or cyclohexane-1R,2R-diamine, dach, series 2, L = aromatic carboxylate of different chain length, i.e. –OCO(CH2)nC6H5, n = 0 (a), 1 (b), and 2 (c)) were synthesized and fully characterized, including X-ray structure analysis of one of them. The antiproliferative activity of the complexes was evaluated against a panel of eight human cancer cell lines, proving to be at the nanomolar level for the platinum-sensitive A2780 and at the sub-micromolar level for the chemoresistant mesothelioma cell lines. In contrast with Pt(IV) complexes bearing aliphatic carboxylates, whose antiproliferative potency increases with the number of carbon atoms, a clear structure–activity relationship cannot be drawn in the bis(benzoato) series. The inclusion reaction with cyclodextrins (CDs), a widely accepted approach for drug formulation, was performed in order to obtain adducts able to bypass the limitations imposed by the low water solubility of bis(benzoato) complexes. Phase-solubility tests demonstrated that β-CD was able to efficiently solubilize only the very active prototype [Pt(NH3)2Cl2(C6H5COO)2] 1a. Two methods were used to prepare the host–guest inclusion systems (i.e., simple solubilization at room temperature of 1a in solution containing excess of β-CD or thermal reaction with subsequent isolation of a solid adduct) and the resulting adducts were tested for cytotoxicity against the cancer cell lines. The presence of β-CD in solution did not decrease the remarkable antitumor activity of 1a, whereas the solid-state inclusion system underwent extensive aggregation, proving to be detrimental for Pt accumulation in the cells and, therefore, overall cytotoxicity.

A direct aminocatalytic synthesis has been developed for the chemo-, regio-, diastereo-, and enantioselective construction of densely substituted polycyclic carbaldehydes containing fused cyclohexadiene rings. The chemistry utilizes, for the first time, remotely enolizable π-extended allylidenemalononitriles as electron-rich 1,3-diene precursors in a direct eliminative [4+2] cycloaddition with both aromatic and aliphatic α,β-unsaturated aldehydes. The generality of the process is demonstrated by approaching 6,6-, 5,6-, 7,6-, 6,6,6-, and 6,5,6-fused ring systems, as well as biorelevant steroid-like 6,6,6,6,5- and 6,6,6,5,6-rings. A stepwise reaction mechanism for the key [4+2] addition is proposed as a domino bis-vinylogous Michael/Michael/retro-Michael reaction cascade. The utility of the malononitrile moiety as traceless activating group of the dicyano nucleophilic substrates is demonstrated.

With a steadily increasing world population, a more efficient system of food production is of paramount importance. One of the major causes of food spoilage is the presence of fungal pathogens and the production and accumulation of mycotoxins. In the present work we report a study on the activity of a series of functionalized thiosemicarbazones (namely cuminaldehyde, trans -cinnamaldehyde, quinoline-2-carboxyaldehyde, 5-fluoroisatin thiosemicarbazone and 5-fluoroisatin N 4 -methylthiosemicarbazone), as antifungal and anti-mycotoxin agents, against the two major genera of cereal mycotoxigenic fungi, i.e. Fusarium and Aspergillus . These thiosemicarbazones display different patterns of efficacy on fungal growth and on mycotoxin accumulation depending on the fungal species. Some of the molecules display a greater effect on mycotoxin synthesis than on fungal growth.

The first example of catalytic, enantioselective hy- pervinylogous Mukaiyama aldol reaction (HVMAR) involving multiply unsaturated 2-silyloxyindoles is reported. The reac- tion utilizes a chiral Lewis base-catalyzed Lewis acid-mediat- ed technology to deliver homoallylic 3-polyenylidene 2-oxin- doles with extraordinary levels of regio-, enantio-, and geo- metrical selectivity. This work highlights a subtle yet decisive influence of the indole N-substituents on the propagation of the vinylogous reactivity space of the donor substrates up to ten bonds away from the origin of the vinylogy effect. Analysis of the 13 C NMR chemical shifts of the C-w remote site within homologous silyloxyindole donors enabled ra- tionalization of the results and easy qualitative prediction of the HVMAR reactivity/inertia toward a given aldehyde acceptor.

In this paper, citronellal, vanillin and pyridoxal thiosemicarbazones were modified with polar substituents, namely ethylmorpholine and glucose, to increase their polarity and compare the effects of these moieties on their biological activity. Altogether, nine ligands were synthesized and for each of them also their copper(II) and nickel(II) complexes were prepared and used for the biological tests. Eventually, assays on proliferation inhibition were conducted using leukemic cell line U937, already used as a model for previous citronellal thiosemicarbazone tests. Biological tests were also performed on solid tumor cell line HT29. From the first screenings, two of the metal complexes showed remarkable interesting properties, and, therefore, were also tested for histosensitivity.

The issue of food contamination by aflatoxins presently constitutes a social emergency, since they represent a severe risk for human and animal health. On the other hand, the use of pesticides has to be contained, since this generates long term residues in food and in the environment. Here we present the synthesis of a series of chelating ligands based on the thiosemicarbazone scaffold, to be evaluated for their antifungal and antiaflatoxigenic effects. Starting from molecules of natural origin of known antifungal properties, we introduced the thio- group and then the corresponding copper complexes were synthesised. Some molecules highlighted aflatoxin inhibition in the range 67–92% at 100 μM. The most active compounds were evaluated for their cytotoxic effects on human cells. While all the copper complexes showed high cytotoxicity in the micromolar range, one of the ligand has no effect on cell proliferation. This hit was chosen for further analysis of mutagenicity and genotoxicity on bacteria, plants and human cells. Analysis of the data underlined the importance of the safety profile evaluation for hit compounds to be developed as crop-protective agents and at the same time that the thiosemicarbazone scaffold represents a good starting point for the development of aflatoxigenic inhibitors.