701 research outputs found
Rodriuez-Arguelles MC, Belicchi errari M, Bisceglie F, Pelizzi C, Pelosi G, Pinelli S, Sassi M
No full textDNA and BSA Interaction Studies and Antileukemic Evaluation of Polyaromatic Thiosemicarbazones and Their Copper Complexes
No full textSome ten million cancer deaths occurred in 2020, highlighting the fact that the search for new anticancer drugs remains extremely topical. In the search for new coordination compounds with relevant biological properties, the choice of a metal ion is important for the design of the complex. In this regard, copper plays a peculiar role, thanks to its distinct properties. Thiosemicarbazones are, analogously, a unique class of ligands because they are easily modifiable, and therefore, extremely versatile in terms of modulating molecular properties. In this work, we synthesized and characterized, by means of X-ray diffraction, four new naphthaldehyde and anthraldehyde thiosemicarbazone derivatives and their copper complexes to be used in interaction studies with biological systems. The objective was to evaluate the antileukemic activity of these compounds. Reactions of these ligands with Cu(II) salts produced unexpected oxidation products and the isolation of Cu(I) metal complexes. One ligand and its related Cu(I) complex, which is stable in physiological conditions, were subjected to in vitro biological tests (UV-Vis and CD titration). An important interaction with DNA and an affinity toward BSA were observed in FT-IR experiments. Preliminary in vitro biological tests against a histiocytic lymphoma cell line revealed an interestingly low IC50 value, i.e., 5.46 μM, for the Cu(I) comple
Short-term exit from pandemic restrictions: did European countries’ speed converge?
No full textConcurrently with the end of the second wave of the coronavirus pandemic, European democracies have progressively relaxed the restrictions on social mobility following the decrease in disease indexes. Did the exit speed from pandemic restrictions substantially differ across governments? This paper intends to analyze this intriguing issue, by investigating whether any convergent response of EU countries did emerge. To this aim, a convergence log-t test is performed on a panel of 25 European countries. Five different clubs emerge which suggest spatially distributed trends for relaxing stringency measures, suggesting the absence of a common European strategy to escape from the first wave pandemic. Additionally, we provide evidence of the role that economic, political, and health variables exert on these different exit strategies
Study of Topoisomerase IIa inhibitors as potential anti-cancer drugs
No full textTopoisomerase II is an essential enzyme that is required for every process that involves the opening of DNA double helix: it helps to regulate under- and overwinding and removes knots and tangle. In order to carry out its function, topoisomerase II generates transient double stranded breaks in DNA. Vertebrate species encode two types of topoisomerase II: IIα and IIβ. Topoisomerase IIα is essential for cellular proliferation and is typical of the G2/M phase. Each subunits of this homodimeric enzyme is composed of two functionally distinct domains, the ATP-binding domain and the DNA cleavage-religation domain, that require respectivley one ATP molecule and two metal ions (Mg2+).
TopoII has been widely exploited as target for anti-tumor drugs. To this aim, we analyzed two classes of compounds, isatin and quinoline thiosemicarbazone derivatives, by means of the molecular docking technique, trying to understand their mechanism of action. Using the Autodock4 software package we investigated the affinity and the binding mode of these compounds in the functional sites of both domains and we compared the results with experimental data obtained in cells and on the pure enzyme in vitro. Copper complexes of both classes of compounds were also studied, which experimentally were found to have a higher inhibitory effect on tumor cells.
Despite of the similarity of their chemical structure with that of ATP, the quinoline derivatives and the corresponding copper complexes did not show, in the ATP-binding site, a binding energy comparable with that of the endogenous ligand, nor a preferred position. This led us to exclude this site as competitive binding site for our compounds. For this reasons, we tried to test all the quinoline compounds in the cleavage site, taking into account the presence of a cleaved DNA fragment. The results showed that only copper complexes had good binding energy and clustered conformations, with the metal atom bound to the phosphate group of broken DNA. This suggested us a possible interference on the successive DNA ligation. In addition, we identified the two copper complexes with the greatest affinity, in close agreement with experimental results.
The results obtained for isatin derivatives seem to indicate a less favoured binding energy in the cleavage site, even if they still interact with the DNA phosphate group. Docking simulations are still in progress into the ATP-binding site to compare the results
Antiproliferative Activity and DNA Interaction Studies of a Series of N4,N4-Dimethylated Thiosemicarbazone Derivatives
No full text: The exploitation of bioactive natural sources to obtain new anticancer agents with novel modes of action may represent an innovative and successful strategy in the field of medicinal chemistry. Many natural products and their chemical analogues have been proposed as starting molecules to synthesise compounds with increased biological potential. In this work, the design, synthesis, and characterisation of a new series of N4,N4-dimethylated thiosemicarbazone Cu(II), Ni(II), and Pt(II) complexes are reported and investigated for their in vitro toxicological profile against a leukaemia cell line (U937). The antiproliferative activity was studied by MTS assay to determine the GI50 value for each compound after 24 h of treatment, while the genotoxic potential was investigated to determine if the complexes could cause DNA damage. In addition, the interaction between the synthesised molecules and DNA was explored by means of spectroscopic techniques, showing that for Pt and Ni derivatives a single mode of action can be postulated, while the Cu analogue behaves differently
Discovery of antibacterial manganese(i) tricarbonyl complexes through combinatorial chemistry
No full text: The continuous rise of antimicrobial resistance is a serious threat to human health and already causing hundreds of thousands of deaths each year. While natural products and synthetic organic small molecules have provided the majority of our current antibiotic arsenal, they are falling short in providing new drugs with novel modes of action able to treat multidrug resistant bacteria. Metal complexes have recently shown promising results as antimicrobial agents, but the number of studied compounds is still vanishingly small, making it difficult to identify promising compound classes or elucidate structure-activity relationships. To accelerate the pace of discovery we have applied a combinatorial chemistry approach to the synthesis of metalloantibiotics. Utilizing robust Schiff-base chemistry and combining 7 picolinaldehydes with 10 aniline derivatives, and 6 axial ligands, either imidazole/pyridine-based or solvent, we have prepared a library of 420 novel manganese tricarbonyl complexes. All compounds were evaluated for their antibacterial properties and 10 lead compounds were identified, re-synthesised and fully characterised. All 10 compounds showed high and broad activity against Gram-positive bacteria. The best manganese complex displayed low toxicity against human cells with a therapeutic index of >100. In initial mode of action studies, we show that it targets the bacterial membrane without inducing pore formation or depolarisation. Instead, it releases its carbon monoxide ligands around the membrane and inhibits the bacterial respiratory chain. This work demonstrates that large numbers of metal complexes can be accessed through combinatorial synthesis and evaluated for their antibacterial potential, allowing for the rapid identification of promising metalloantibiotic lead compounds
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