The halido- alpha-bridge cleavage reactions between [Pd( C 2 ,N -tetrox)( mu-Cl)] 2 precursor (tetrox = E- alpha tetralone oxime) with phosphines, in 1:2 molar ratio, have afforded mononuclear cyclopalladated compounds of the type [PdCl( C 2 ,N -tetrox)(L)] { L = triphenylphosphine ( 1 ); tris(4-methylphenyl)phosphine ( 2 ); tris(4-fluorophenyl)phosphine ( 3 ) and tris(4-methoxyphenyl)phosphine ( 4 )}. The compounds have been characterized by elemental analyses, infrared (FT-IR) and 1 H, 13 C{ 1 H} and 31 P{ 1 H}-NMR spectroscopies. The molecular structure of 3 has been determined by single crystal X-ray diffraction (SC-XRD) and the Hirshfeld Surface calculation (HS) has been performed. The antiproliferative activity of compounds 1-4 has been evaluated against breast (MCF-7) and lung (A549) human cancer cells, and human lung fibroblast (MRC-5). All cyclopalladated compounds have been more active than cisplatin against MCF-7 cells, with IC 50 values ranging from 19 to 26 mu M. Binding experiments involving compound 3 with ct-DNA and human serum albumin (HSA) have been carried out using spectroscopic techniques. The interaction between compound 3 and HSA has been studied by means of molecular docking. (c) 2021 Elsevier B.V. All rights reserved.

As part of our continuing efforts to discover new bioactive compounds from endophytic fungal sources, we have investigated the extract of the Paraphaeosphaeria sporulosa F03 strain. The study led to the isolation of four new 3-methyl-isoquinoline alkaloids ( 1 - 4 ) and four known polyketides ( 5 - 8 ). The structures of compounds 1 - 4 were elucidated by 1D and 2D NMR experiments and HRMS analysis. The absolute configuration of 4 was determined by comparison of its experimental electronic circular dichroism spectrum with calculated data. Compounds 1 - 4 exhibited antifungal activity with minimal inhibitory concentration values ranging from 6.25 - 50 mu g/mL against six Candida species but they did not present any cytotoxic activity against the human tumor cell lines A549 (lung), MCF-7 (breast), and HepG2 (hepatocellular). In addition, compound 4 exhibited antiplasmodial activity in the low micromolar range (IC (50) = 4 mu M).

Novel silver(i) complexes of the type [AgCl(PPh3)2(L)] {PPh3 = triphenylphosphine; L = VTSC = 3-methoxy-4-hydroxybenzaldehyde thiosemicarbazone (1); VMTSC = 3-methoxy-4-[2-(morpholine-1-yl)ethoxy]benzaldehyde thiosemicarbazone (2); VPTSC = 3-methoxy-4-[2-(piperidine-1-yl)ethoxy]benzaldehyde thiosemicarbazone (3)} were synthesized and fully characterized by spectroscopic techniques. The molecular structures of complexes 2 and 3 were determined by single crystal X-ray diffraction. Compounds 1-3 exhibited appreciable cytotoxic activity against human tumor cells (lung A549, breast MDA-MB-231 and MCF-7) with IC50 values in 48 h of incubation ranging from 5.6 to 18 μM. Cellular uptake studies showed that complexes 1-3 were efficiently internalized after 3 hours of treatment in MDA-MB-231 cells. The effects of complex 1 on the cell morphology, cell cycle, induction of apoptosis, mitochondrial membrane potential (Δψm), and reactive oxygen species (ROS) production have been evaluated in triple negative breast cancer (TNBC) cells MDA-MB-231. Our results showed that complex 1 induced typical morphological alterations of cell death, an increase in cells at the sub-G1 phase, apoptosis, and mitochondrial membrane depolarization. Furthermore, DNA binding studies evidenced that 1 can bind to ct-DNA and does so without modifying the B-structure of the DNA, but that the binding is weak compared to that of Hoechst 33258.

New silver(i) compounds containing 2-formylpyridine-N(4)-R-thiosemicarbazones and 1,10-phenanthroline (phen) were synthesized and characterized by spectroscopic techniques (IR and NMR), elemental analysis, ESI-MS and molar conductance measurements. In these complexes, both phen and thiosemicarbazone ligands are coordinated in a chelating bidentate fashion. Compounds 1-3 not only showed good in vitro antiproliferative activity against human lung (A549) and breast tumor cells (MDA-MB-231 and MCF-7), with IC50 values ranging from 1.49 to 20.90 μM, but were also demonstrated to be less toxic towards human breast non-tumor cells (MCF-10A). Cellular uptake studies indicated that compounds 1-3 were taken up by the MDA-MB-231 cells in 6 hours. Cell death assays in the MDA-MB-231 cells were conducted with compound 1 aiming to evaluate its effects on cell morphology, induction of apoptosis, the cell cycle, reactive oxygen species (ROS) formation and mitochondrial membrane potential (Δψm). Compound 1 caused morphological changes, such as cell shrinkage and rounding, increased the sub-G1 phase population, and induced apoptotic cell death, ROS formation and loss of mitochondrial membrane potential (Δψm). DNA binding results revealed that 1 interacted with the ct-DNA minor groove. Complexes 1-3 also exhibited good in vitro activity against M. tuberculosis H37Rv, with MIC values ranging from 3.37 to 4.65 μM.

A new series of silver compounds could be of interest on designing new drugs for the treatment of leishmaniasis. The compounds [Ag(phen)(imzt)]NO3(1), [Ag(phen)(imzt)]CF3SO3(2), [Ag(phen)2](BF4)·H2O (3), [Ag2(imzt)6](NO3)2(4), and imzt have been synthesized and evaluated in vitro for antileishmanial activity against Leishmania. (L.) amazonensis (La) and L. (L.) chagasi (Lc), and two of them were selected for in vivo studies. In addition to investigating the action on Leishmania, their effects on the hydrogen peroxide production and cysteine protease inhibition have also been investigated. As for antileishmanial activity, compound (4) was the most potent against promastigote and amastigote forms of La (IC50 = 4.67 and 1.88 μM, respectively) and Lc (IC50 = 9.35 and 8.05 μM, respectively); and comparable to that of amphotericin B, reference drug. Beside showing excellent activity, it also showed a low toxicity. In the in vivo context, compound (4) reduced the number of amastigotes in the liver and spleen when compared to the untreated group. In evaluating the effect of the compounds on Leishmania, the level of hydrogen peroxide production was maintained between the lag and log phases; however, in the treatment with compound (4) it was possible to observe a reduction of 25.44 and 49.13%, respectively, in the hydrogen peroxide rates when compared to the lag and log phases. It was noticed that the presence of a nitrate ion and imzt in compound (4) was important for the modulation of the antileishmanial activity. Thus, this compound can represent a potentially new drug for the treatment of leishmaniasis.

Bridge splitting reactions between [Pd(C2,N-dmba)(μ-X)]2 (dmba = N,N-dimethylbenzylamine; X = Cl, I, N3, NCO) and 2,6-lutidine (lut) in the 1:2 molar ratio at room temperature afforded cyclopalladated compounds of general formulae [Pd(C2,N-dmba)(X)(lut)] {X = Cl- (1), I-(2), NNN-(3), NCO-(4)}, which were characterized by elemental analyses and infrared (IR), 1H NMR spectroscopy. The molecular structures of all synthesized palladacycles have been solved by single-crystal X-ray crystallography. The cytotoxicity of the cyclopalladated compounds has been evaluated against a panel of murine {mammary carcinoma (4T1) and melanoma (B16F10-Nex2)} and human {melanoma (A2058, SK-MEL-110 and SK-MEL-5) tumor cell lines. All complexes were about 10 to 100-fold more active than cisplatin, depending on the tested tumor cell line. For comparison purposes, the cytotoxic effects of 1-4 towards human lung fibroblasts (MRC-5) have also been tested. The late apoptosis-inducing properties of 1-4 compounds in SK-MEL-5 cells were verified 24 h incubation using annexin V-Fluorescein isothiocyanate (FITC)/propidium iodide (PI). The binding properties of the model compound 1 on human serum albumin (HSA) and calf thymus DNA (ct-DNA) have been studied using circular dichroism and fluorescence spectroscopy. Docking simulations have been carried out to gain more information about the interaction of the palladacycle and HSA. The ability of compounds 1-4 to inhibit the activity of cathepsin B and L has also been investigated in this work.