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Organotin(IV) complexes represent promising drugs in medicinal chemistry for their potential use in cancer therapy. We recently reported synthesis and characterization of a new organotin(IV) complex of ferulic acid (FA), tributyltin(IV) ferulate (TBT-F), showing its antitumor action in colon cancer cells. Here we provide evidence that the efficacy of this compound is strongly potentiated by the proteasome inhibitor bortezomib (BTZ). While low concentrations of tributyltin(IV) ferulate alone promoted autophagy without reducing cell viability, combination of the two compounds markedly affected colon cancer cell viability, cell morphology and exasperated endoplasmic reticulum (ER) stress, as revealed by a dramatic increase in Grp78 ER stress marker and consequent unfolded protein response (UPR) pathway components including PERK, eIF2α and downstream transcription factor CHOP. Our data also indicated that ER stress promoted by the TBT-F/BTZ combination leads to apoptosis, as shown by caspase 3 and caspase 7 activation, PARP cleavage, increase in p53 levels, chromatin condensation and prevention of the TBT-F effect by the caspase inhibitor zVAD-fmk.

The icon Virgin Hodegetria, now in Santa Maria Nuova Cathedral in Monreale near Palermo (Italy), probably dates from the beginning of thirteen century could be considered one of the earliest examples of medieval icon in Sicily. The icon is distinguished from other southern icons by the strong Byzantine matrix and by its size (169x131x3 cm). Since 2015, the icon is part of the Arab-Norman Palermo UNESCO Heritage. This paper will deal with historical and scientific investigations on the icon to better understand the painting materials, the executive technique and to resolve question about on-going restoration in planning a complex conservation project. Examination of the icon was both non-invasive (IR false colour, IR b/w, UV fluorescence) and micro invasive (optical microscopy, scanning electron microscopy with energy dispersive X-ray spectroscopy, FT-IR spectroscopy and micro-Raman spectroscopy). The executive technique appears to be similar to that used in 13th century according to Italian painting tradition: canvas support is present between the wooden panel and the gypsum/glue-based preparatory layer. The underdrawing includes the occurrence of dark grey accurate lines that seem to have been applied by brush. Silver leaf was used as a background of the paintings and in the haloes of the Virgin and Child without bole layer preparation. Mineral pigments (red and yellow ochre, green earth pigments), carbon and bone black, Cu-based pigments, azurite, indigo, orpiment/realgar, lead white, vermillion were mixed with egg-yolk medium. The presence of several not original paint layers, gilding and varnishes belonging to different previous restorations required a conservation treatment able to return to the original iconography and the stylistic specificities of the masterpiece of Monreale.

Infrared (IR) absorption spectroscopy is one of the most important analytical techniques available to study different kinds of samples including solids, semisolids, biological materials, films, liquids, solutions, and gases. IR spectroscopy not only uses the so-called infrared absorption, but also other techniques such as the attenuated total reflection method, diffuse reflectance method, reflection-absorption method, photoacoustic spectroscopy, and emission spectroscopy. IR spectroscopy is a technique based on the vibrations of the atoms of a molecule. An infrared spectrum is obtained by passing infrared radiation through a sample and determining what fraction of the incident radiation is absorbed at a particular energy. Fourier transform infrared (FTIR) spectrometry is based on the use of an interferometer. A common FTIR spectrometer consists of a source, an interferometer, a sample holder, and a detector. Transmission spectroscopy is based upon the absorption of infrared radiation at specific wavelengths as it passes through a sample.

Organotin(IV) compounds have found their place among a class of non-platinum chemotherapeutic metallo-pharmaceuticals exhibiting good antitumor activity. The cytotoxicity induced by the different kinds of organotins has been related to several mechanism. In this review we report our last decade research activity concerning the synthesis and chemical characterization of new organotin(IV) derivatives containing epigenetic modulator ligand by using, FT-IR, Mössbauer spectroscopy, 119Sn{1H} cross polarization magic angle spinning, electrospray ionization mass spectroscopy, UV–Vis, 1H, 13C{1H} and 119Sn{1H} NMR spectroscopy and density functional theory calculations. The first aim of the biological studies was to evaluate the effects exerted by organotin(IV) complexes in comparison with corresponding free ligands on a panel of different cancer cell lines, including human HepG2 hepatoma cells, HCT116 colorectal carcinoma cells and MDA-MB-231 breast cancer cells. We provide evidence that the compounds, generally, exert significant cytotoxic activity in cancer cells even at nanomolar (nM) or micromolar (μM) range concentrations. We also evaluated the biochemical pathways underlining these effects and the epigenetic activity of the compounds in the coordinated form compared to their parental constituents.

In this study the Madonna del Soccorsoo della Mazza wooden sculpture has been analysed by an interdisciplinary and integrated approach. The polychrome sculpture, dating back to the 18thcentury, comes from the church of the Madonna del Soccorso or della Mazza (1604) situated in Via Maqueda, in Palermo and it was placed on the main recess of the altar. All steps of the conservation project, from the preliminary study to the choice of materials and the restoration procedures have been accompanied and supported by diagnostic and scientific analysis. In order to evaluate the state of conservation of the sculpture and the technique employed to construct the support, computer tomography study was performed. Optical microscopy allowed to identify the wooden species and to verify the presence of microbial colonization or insect infestation. Scanning electron microscopy, combined with energy dispersive X-ray analysis (SEM/EDS), as well as XRF (X-ray fluorescence spectroscopy), were used to characterize paint stratigraphy and pigments. Sampling by sterile swabs and in vitro microbial culture has been performed to obtain the biological colonization.

Melanoma is the most aggressive and deadly form of skin cancer, which is largely due to its propensity to metastasize. Therefore, with the aim to inhibit the growth and the metastatic dissemination of melanoma cells and to provide a novel treatment option, we studied the effects of the melanoma treatment with two organotin(IV) complexes of the meso-tetra(4-sulfonato-phenyl)porphine, namely (Bu2Sn)2TPPS and (Bu3Sn)4TPPS. In particular, we showed that nanomolar concentrations of (Bu2Sn)2TPPS and (Bu3Sn)4TPPS are sufficient to inhibit melanoma cell growth, to increase the expression of the full-length poly (ADP-ribose) polymerase (PARP-1), to induce the cell cycle arrest respectively at G2/M and G0/G1 through the inhibition of the Cyclin D1 expression and to inhibit cell colony formation. Nanomolar concentrations of (Bu2Sn)2TPPS and (Bu3Sn)4TPPS are also sufficient to inhibit the melanoma cell migration and the expression of some adhesion receptors. Moreover, we report that (Bu2Sn)2TPPS and (Bu3Sn)4TPPS act downstream of BRAF, mainly bypassing its functions, but targeting the STAT3 signalling protein. Finally, these results suggest that (Bu2Sn)2TPPS and (Bu3Sn)4TPPS may be effective therapeutic strategies for their role in the inhibition of melanoma growth and migration.

Organotin compounds represent potential cancer therapeutics due to their pro-apoptotic action. We recently synthesized the novel organotin ferulic acid derivative tributyltin (IV) ferulate (TBT-F) and demonstrated that it displays anti-tumor properties in colon cancer cells related with autophagic cell death. The purpose of the present study was to elucidate the mechanism of TBT-F action in colon cancer cells. We specifically show that TBT-F-dependent autophagy is determined by a rapid generation of reactive oxygen species (ROS) and correlated with endoplasmic reticulum (ER) stress. TBT-F evoked nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated antioxidant response and Nrf2 silencing by RNA interference markedly increased the anti-tumor efficacy of the compound. Moreover, as a consequence of ROS production, TBT-F increased the levels of glucose regulated protein 78 (Grp78) and C/EBP homologous protein (CHOP), two ER stress markers. Interestingly, Grp78 silencing produced significant decreasing effects on the levels of the autophagic proteins p62 and LC3-II, while only p62 decreased in CHOP-silenced cells. Taken together, these results indicate that ROS-dependent ER stress and autophagy play a major role in the TBT-F action mechanism in colon cancer cells and open a new perspective to consider the compound as a potential candidate for colon cancer treatment.

This work presents the first reported imbibition mechanism of femtoliter (fL)-scale droplets produced by microchannel cantilever spotting (μCS) of DNA molecular inks into porous substrates (hydrophilic nylon). Differently from macroscopic or picoliter droplets, the downscaling to the fL-size leads to an imbibition process controlled by the subtle interplay of evaporation, spreading, viscosity, and capillarity, with gravitational forces being quasi-negligible. In particular, the minimization of droplet evaporation, surface tension, and viscosity allows for a reproducible droplet imbibition process. The dwell time on the nylon surface permits further tuning of the droplet lateral size, in accord with liquid ink diffusion mechanisms. The functionality of the printed DNA molecules is demonstrated at different imbibed oligonucleotide concentrations by hybridization with a fluorolabeled complementary sequence, resulting in a homogeneous coverage of DNA within the imbibed droplet. This study represents a first step toward the μCS-enabled fabrication of DNA-based biosensors and microarrays into porous substrates.

Dip-pen lithography (DPL) technique has been employed to develop a new flexible biosensor realized on nylon with the aim to detect the activity of human topoisomerase. The sensor is constituted by an ordered array of a DNA substrate on flexible nylon supports that can be exploited as a drug screening platform for anticancer molecules. Here, we demonstrate a rapid protocol that permits to immobilize minute quantities of DNA oligonucleotides by DPL on nylon surfaces. Theoretical and experimental aspects have been investigated to successfully print DNA oligonucleotides by DPL on such a porous and irregular substrate.

Ferulic acid (FA) is a natural phenolic phytochemical that has low toxicity and exhibits therapeutic effects against various diseases, behaving as an antioxidant. FA also displays modest antitumor properties that have been reported at relatively high concentrations. With the aim of improving the anti-tumor efficacy of FA, we synthesized the novel compound tributyltin(IV) ferulate (TBT-F). The coordination environment at the tin center was investigated spectroscopically. Following synthesis, chemical characterization and computational analysis, we evaluated TBT-F effects in colon cancer cells. The results showed that TBT-F, at nanomolar range concentrations, was capable of reducing the viability of HCT116, HT-29 and Caco-2 colon cancer cells. On the other hand, FA was completely inefficacious at the same treatment conditions. Cell viability reduction induced by TBT-F was associated with G2/M cell cycle arrest, increase in membrane permeabilization and appearance of typical morphological signs. TBT-F-induced cell death seemed not to involve apoptotic or necroptotic markers whereas autophagic vacuoles appearance and increase in LC3-II and p62 autophagic proteins were observed after treatment with the compound. The autophagy inhibitor bafylomicin A1 markedly prevented the effect of TBT-F on colon cancer cells, thus indicating that autophagy is triggered as a cell death process. Taken together, our results strongly suggest that the novel ferulic derivative TBT-F is a promising therapeutic agent for colon cancer since it is capable of triggering autophagic (type-II) cell death that may be important in case of resistance to classic apoptosis.

The aim of the present research is to investigate the constitutive materials and the execution techniques of San Vito wooden pulpit from Museo Diocesano of Palermo (Italy) and to provide helpful information to dating it in addition to technical, historical and artistic evaluations. The pulpit, attributed to unknown artist, belongs to the decorative arts and the most relevant feature is its double dating, in addition to the singular painting technique: it has a linear structure typical of XIXth century and three polychrome and gilded panels probably dated to the end of XVIIth century. This paper describes the application of analytical techniques (imaging diagnostics techniques, Scanning Electron Microscopy coupled with X-ray Energy Dispersive Spectroscopy and Fourier Transform Infrared Spectroscopy) to better understand and characterize the pulpit, both support and decoration, useful to plan and perform the correct restoration. They revealed a proteinaceous pittoric layer for the linear structure, without a preparation. The panels are entirely covered by gold leaf applied on a preparation composed by a first white layer with gypsum and animal glue and a second one with bole. The traditional pigments, red and green lacquers using oil as binding medium are applied on gold leaf by thin and transparent brushstrokes.

PubMedID: 27393277 The interaction of the diorgano- and triorganotin(IV) derivatives of meso-tetra-(4-sulfonatophenyl)porphine (Me2Sn)2TPPS, (Bu2Sn)2TPPS, (Me3Sn)4TPPS and (Bu3Sn)4TPPS to natural DNA was analysed (together with free meso-tetra-(4-sulfonatophenyl)porphine (TPPS4 -) for comparison purposes). Particular attention was paid to (Bu3Sn)4TPPS, a species that shows significant cellular action. Preliminary tests were done on the solution properties of the organotin(IV) compounds (pKA and possible self-aggregation). Spectrophotometric and spectrofluorometric experiments showed that all the investigated organotin(IV) derivatives strongly interact with DNA, the binding energy depending on the dye steric hindrance. In all cases experimental data concur in indicating that external binding mode prevails. Interestingly, fluorescence quenching and viscosity experiments show that the Bu-containing species, and in particular (Bu3Sn)4TPPS, are able to noticeably alter the DNA conformation. © 2016 Elsevier Inc. Università degli Studi di Palermo “la Caixa” Foundation: OSLC-2012-007 PRA_2015_0038 Ministerio de Economía, Industria y Competitividad, Gobierno de España: MINECO CTQ2014-58812-C2-2-R The financial support by PRA 2015 of the University of Pisa , project PRA_2015_0038 , by Obra Social “la Caixa” , project OSLC-2012-007 , by the Ministerio de Economia y Competividad - Gobierno de España , project MINECO CTQ2014-58812-C2-2-R , and by Università degli Studi di Palermo Grant ORPA07SLXE are gratefully acknowledged. Appendix A

The Ritratto muliebre, referring to Venus, is a panel painting, oil on wood, attributed to unknown artist and probably dated to the second half of 16th century, today conserved in the Galleria Interdisciplinare Regionale della Sicilia—Palazzo Mirto of Palermo. The aim of this research was to assess the techniques used to decorate the wooden painting and to verify the state of conservation of the artwork's materials but also to identify the previous treatments. This study was the essential condition to plane and perform the correct restoration. For this reason, an integrated analytical approach based on the use of non-invasive and micro-invasive techniques was used, with the aim to obtain a characterization of the wooden panel, to elucidate the painting technique, including the stratigraphic sequence of the pigments and the organic binders, the state of preservation, the possible decay processes, and the possible additions made during previous restorations. In addition to the imaging diagnostics techniques and the microchemical spot tests, micro-fragments of the painted material, original or not, were analyzed by several analytical techniques: optical microscopy, scanning electron microscopy (SEM-EDAX), FT-IR spectroscopy, and X-ray photoelectron spectroscopy (XPS). The results of all analyses revealed that the portrait is a small panel painting made by an unknown painter in the second half of 16th century, with a traditional painting technique: a single wooden panel, two preparatory layers (“ammannitura”), a sort of priming (“imprimitura”), an underdrawing, a paint layer composed of oil as binding medium and pigments common in 16th century.

Eight R2Sn(IV)-D-aldonate complexes [(R = Me, Bu; D-aldonate = D-galactonate2− (Galn), D-Gluconate2− (Glun), D-Gulonate2− (Guln), D-Ribonate2− (Ribn)], five of which are new derivatives, have been synthesized and structurally characterized both in solid and solution state by IR, 119Sn Mossbauer and 1H, 13C, 119Sn NMR spectroscopies, showing that ligands act as dianonic chelating agents. In solution phase, NMR data suggest that the bidentate chelation is attained by the O1 carboxylate and the vicinal O2 alkoxide atoms, which can be dynamically extended to a third binding site (O4) competing with O2. In Me2Sn(IV)-D-gluconate complex the occurrence of a self-association process leading to a dimeric species was also observed. Histopathological studies on different organs of Liza saliens showed that the dibutyltin(IV)-D-aldonate complexes, although preserving the defense immunity system, exhibit a specific toxicity on some target cells and organs. The toxicity of such complexes has been compared with respect to the effects of a previous study with tributyltin(IV) chloride solutions. Copyright © 2008 John Wiley & Sons, Ltd.

In the recent past years, interest in the environmental impact of organotin(IV) compounds has risen markedly. Considering that most data in the scientific literature refers to the animal kingdom and not to higher plants cells, we tested the effects of organotin compounds on vascular plant cells, by studying the interaction of tributyltin chloride (TBTCl) with Allium cepa, Solanun tuberosum and Solanum melongena, vascular plants that are directly involved in the human food chain. The TBTCl effects on mitotic metaphase plates, on pollen grains and on both microtubers and adult tuber parenchymatic cells were investigated and the concentrations of TBTCl inside the treated parenchymatic cells were determined through ICP-mass spectrometry. Oxygen and chlorophyll productions were also determined. The obtained results showed that TBTCl influenced not only morphology, but also the physiology of the vegetable cells since, despite the low concentrations used, the stress the cells were submitted to was experimentally confirmed. Moreover, the increase in the tin concentration in the cells, with increasing incubation time, showed that TBTCl possesses a very high capacity to be bioaccumulated and, as a consequence, it is able to enter the food chain. Copyright © 2006 John Wiley & Sons, Ltd.

This work deals with the synthesis, the chemical characterization of dibutyltin(IV) complex of caffeic acid (Bu2Sn(IV)HCAF, caf1) and its cytotoxic action on tumor cells. The coordination environment at the tin center was investigated by FTIR, (119)Sn{(1)H} cross polarization magic angle spinning, electrospray ionization mass spectroscopy in the solid state and UV-vis, fluorescence and (1)H, (13)C and (119)Sn NMR spectroscopy in solution phases. Density functional theory study confirmed the proposed structures in solution phase and indicated the most probably stable conformation. The effects on viability of breast cancer MDA-MB231, colorectal cancer HCT116, hepatocellular carcinoma HepG2 and Chang liver cells, an immortalized non-tumor hepatic cell line, have been investigated. The effect of a variation in structure of caf1 was found to lead to a change in the respective antiproliferative properties: caf1 induces loss of viability in HCT116, MDA-MB-231, and HepG2; the complex shows only moderate effects in non-tumor Chang liver cells. caf1 exerts lower cytotoxic activity than Bu2SnCl2, suggesting that the binding with H3CAF modulates the marked cytotoxic activity exerted by Bu2SnCl2; caf1 displays a considerably more pronounced antitumoural effect towards cell lines than caffeic acid. It is known that caffeic acid can modulate DNA (cytosine-5)-methyltransferases 1 (DNMT1) mediated DNA methylation. In this paper we demonstrate that caf1 treatment was able to induce a time-dependent reduction of global DNA methylated status. This effect was also confirmed by a concomitant reduction DNMT1 expression level. The effect induced by caf1 was more evident not only with respect to untreated cells but also compared to H3CAF treated cells.

Nowadays artworks traditionally included in the category of applied or decorative arts are considered at the same level of fine arts getting over the old definition of minor art. According to this consideration an increasing number of studies and paper deals with the decorative arts and the Observatory for Decorative Arts in Italy “Maria Accascina” (OADI) was settled within the University of Palermo in order to study them. Nevertheless most studies deal with artistic and historic issues of applied arts and just few concern with the technique used, at least in the southern part of Italy. This paper is a systematic research concerning the constitutive materials and the executive techniques of wooden frames production in Sicily, a kind of artworks usually underrated and neglected so that often they were substituted or modified and today we don’t have a lot of information or we don’t know the name of their authors. As the frames are works of arts themselves as well as complements of their paintings, in this paper an exploration of several different types found in Sicily has been performed in order to better understand the evolution of shapes, functions, technical characteristics and ornamental models over the centuries. Many decorative techniques have been used on wood, with or without a preparatory layer, by applying pigments and gold or silver leaves and by inlaying ivory or mother-of-pearl, etc. Several organic binding and gluing media have been used: proteinaceous materials, drying oils, waxes, resins and vegetable gums.

This review summarized the literature and own data on the parent organotin(IV) compounds and complexes formed with biologically active ligands.

The histopathological effects of 10−7 and 10−9M tributyltin(IV)chloride,TBTCl, solutions on different Liza saliens organs have been studied by light microscope. The fish were sacrificed after 3–4 h incubation in 10−7M TBTCl solution or after 15 days incubation in 10−9M solution. The observed histopathological changes were dose- and time-dependent. The 10−7M TBTCl concentration resulted in major damage to the gill epithelium, indicating that TBTCl primarily interfered with the respiration, osmoregulation, acid balance and nitrogenous waste excretion processes. After incubation in 10−9M TBTCl solution the fish lived 20 or more days, but many of the organs were altered. Thymus atrophy, reduced spleen and altered head kidney were observed. These histological results indicated that TBTCl interfered with organ immunodefense and altered main metabolic pathways in Liza saliens. The presence of melano-macrophage centers, only in TBT-treated liver and spleen, can be considered a tool to facilitate, with other biomarkers, the detection of alterations by toxicants. Regarding the pancreas activity in 10−7M solutions, it has been noted that, in the exocrine cells, very few zymogen granules were still present and the Langerhans islets were more altered. In 10−9M solution the exocrine pancreatic cells had no granules and the islet cells presented degenerative alterations. In addition, TBTCl, which altered the pancreas and gonad morphology, could again be considered an endocrine disrupter even if biochemical data are still necessary. Finally, the Liza saliens juveniles could be considered an interesting biological model for experiments with contaminants, due to their ease of adaptation to experimental conditions and food chain position. Copyright © 2005 John Wiley & Sons, Ltd.

The toxicity studies of free 5-[(E)-2-(aryl)-1-diazenyll-2-hydroxybenzoic acid and 2-[(E)-2-(3-formyl-4-hydroxyphenyl)-1-diazenyllbenzoic acid and their tri-n-butyltin(IV) complexes were evaluated by using sea urchin early developmental stages as recommended model organisms for toxicity tests. The novel complexes, as the parent tri-n-butyltin(IV) chloride (TBTCl), caused mitosis block and induced high embryonic mortality in sea urchin. Copyright (c) 2005 John Wiley & Sons, Ltd.

Reduction of total lipids (TL) content and significant variations of triglyceride (TG) and phospholipid (PL) fractions were observed as a consequence of exposure of Ciona intestinalis ovaries to tributyltin chloride (TBTCL) solutions. In particular, an evident TG decrease and a PL increase were observed, which probably provoked an increment in membrane fluidity, because of the high concentration of long chain fatty acids and, as a consequence, PL. This could be a cell adaptive standing mechanism towards the pollutants, as observed in Saccharomyces cerevisiae. Also the increase in the content of the polyunsaturated fatty acids (PUFA), important in the synthesis of compounds such as prostaglandine which are present in the ovary in a stress situation, was probably a consequence of a defense mechanism to the stress provoked by the presence of TBTCI. Copyright © 2005 John Wiley & Sons, Ltd.

Dialkyltin(IV) and trialkyltin(IV) complexes of the deacetoxycephalo-sporin-antibiotic cephalexin [7-( d -2-amino-2-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid] (Hceph) have been synthesized and investigated both in solid and solution phase. Analytical and thermogravimetric data supported the general formula Alk 2 SnOHceph · H 2 O and Alk 3 Snceph · H 2 O (Alk=Me, n -Bu), while structural information has been gained by FT-IR, 119 Sn Mossbauer and 1 H, 13 C, 119 Sn NMR data. In particular, IR results suggested polymeric structures both for Alk 2 SnOHceph · H 2 O and Alk 3 Snceph · H 2 O. Moreover, cephalexin appears to behave as monoanionic tridentate ligand coordinating the tin(IV) atom through ester-type carboxylate, as well as through β-lactam carbonyl oxygen atoms and the amino nitrogen donor atoms in Alk 2 SnOHceph · H 2 O complexes. On the basis of 119 Sn Mossbauer spectroscopy it could be inferred that tin(IV) was hexacoordinated in such complexes in the solid state, showing skew trapezoidal configuration. As far as Alk 3 Sn(IV)ceph · H 2 O derivatives are concerned, cephalexin coordinated the Alk 3 Sn moiety through the carboxylate acting as a bridging bidentate monoanionic group. Again, 119 Sn Mossbauer spectroscopy led us to propose a trigonal configuration around the tin(IV) atom, with R 3 Sn equatorial disposition and bridging carboxylate oxygen atoms in the axial positions. The nature of the complexes in solution state was investigated by using 1 H, 13 C and 119 Sn NMR spectroscopy. Finally, the cytotoxic activity of organotin(IV) cephalexinate derivatives has been tested using two different chromosome-staining techniques Giemsa and CMA 3 , towards spermatocyte chromosomes of the mussel Brachidontes pharaonis (Mollusca: Bivalvia). Colchicinized-like mitoses (c-mitoses) on slides obtained from animals exposed to organotin(IV) cephalexinate compounds, demonstrated the high mitotic spindle-inhibiting potentiality of these chemicals. Moreover, structural damages such as ‘chromosome achromatic lesions’, ‘chromosome breakages’ and ‘chromosome fragments’ have been identified through a comparative analysis of spermatocyte chromosomes from untreated specimens (negative controls) and specimens treated with the organotin(IV) complexes.

The morphological aspects of Styela plicata fertilization after treatment with tributyltin(IV) chloride are described by means of scanning and transmission electron microscopy investigations. Alterations have been shown both on female and male gametes; spermatozoa, all the egg envelopes and the mitochondria of the egg cortical cytoplasm are modified in relation to incubation time. As a consequence, the damage to gametes blocks sperm–egg interaction and fertilization does not occur. Copyright © 2003 John Wiley & Sons, Ltd.

The coordination of Me 2 Sn(IV) 2+ (M) to captopril { N -[( S )-3-mercapto-2-methylpropionyl]- l -proline, H 2 (cap), H 2 L} in aqueous solution was studied by means of potentiometric titration, electrospray mass spectrometry, 1 H-NMR spectroscopy and Mossbauer spectroscopy in the pH range 2–11 ( I =0.1 mol dm −3 NaClO 4 , 298 K). The results obtained with these methods proved that only monomeric complexes are formed in solution. In the acidic pH range, species with a metal-to-ligand ratio of 1:1 exist. The neutral complex ML, similarly to the complex Me 2 Sn(cap) crystallized in the same pH range, adopts a tbp structure with eq S − and ax COO − , while, instead of the coordination of the amide CO, observed in the solid state, the other ax position is occupied by a H 2 O molecule. With increasing pH, in the neutral and weakly basic pH range the complexes MLH −1 and ML 2 are formed, in which the COO − group is displaced from the coordination sphere by an OH − and an S − of another ligand, respectively. Biological activity tests on Me 2 Sn(cap) and three further R 2 Sn(IV) captopril complexes showed that n- Bu 2 Sn(cap) and t- Bu 2 Sn(cap) exert toxic activity towards the embryos of Ciona intestinalis , while the ligand itself does not affect the development of the embryos to any significant extent; Me 2 Sn(cap) and Et 2 Sn(cap) produced normal swimming larvae.

Ascidia malaca gametes before fertilization incubated in 10-5 or 10-7 M solutions of tributyltin(IV) chloride, TBTCl, for 3 h appear highly damaged under transmission electron microscopy observation. Also, the fertilization process is affected by the compound: the damaged spermatozoa are present in the vitelline coat and the egg does not cleave. An increase of microbodies, structurally similar to peroxisomes, have been detected in the egg peripheral cytoplasm, probably in relation to their role in alleviating damage to some cellular components. The results have shown that the reproduction of ascidians under unfavourable environmental conditions is prevented. Copyright © 2003 John Wiley & Sons, Ltd..

Novel triorganotin(IV) complexes of two beta-lactamic antibiotics, 6-[D-(-)-beta-amino-p-hydroxyphenyl-acetamido]penicillin (=amoxicillin) and 6-[D-(-)-alpha-aminobenzyl]penicillin (=ampicillin), have been synthesized and investigated both in solid and solution states. The complexes corresponded to the general formula R(3)Sn(IV)antib*H(2)O (R=Me, n-Bu, Ph; antib=amox=amoxicillinate or amp=ampicillinate). Structural investigations about configuration in the solid state have been carried out by interpreting experimental IR and 119Sn Mossbauer data. In particular, IR results suggested polymeric structures both for R(3)Sn(IV)amox.H(2)O and R(3)Sn(IV)amp*H(2)O. Moreover, both antibiotics appear to behave as monoanionic bidentate ligands coordinating the tin(IV) atom through ester-type carboxylate, as well as through the beta-lactamic carbonyl. Evidence that in none of these compounds water molecules were involved in coordination, was provided by thermogravimetric investigations. On the basis of 119Sn Mossbauer spectroscopy it can be inferred that tin(IV) was pentacoordinate in all of the complexes in the solid state, showing an equatorial R(3)Sn(IV) trigonal bipyramidal (tbp) configuration. The nature of the complexes in solution state was investigated by using 1H and 13C nuclear magnetic resonance (NMR) spectroscopy, while an 119Sn spectrum was obtained for n-Bu(3)Sn(IV)amp*H(2)O. Although 1H- and 13C-NMR measurements suggested that in dimethyl sulfoxide (DMSO)-d(6) solution the polymeric structure collapsed, due to a solvolysis process of the beta-lactamic carbonyl bonding to the organometallic moiety, the complexes have been shown to maintain the same trigonal bipyramidal configuration at tin(IV) atom by the coordination of a DMSO molecule. Cytotoxic activity of these novel semisynthetic antibiotic derivatives has been tested towards spermatocyte chromosomes of the mussel Brachidontes pharaonis (Mollusca: Bivalvia) using two different chromosome-staining techniques such as Giemsa and CMA(3). The occurrence of typical colchicinized-like (c-like) mitoses on slides obtained from animals exposed to organotin compounds, directly confirmed the high mitotic spindle-inhibiting potency of these chemicals. In addition, by comparative analysis of spermatocyte chromosomes from untreated specimens (negative controls) and specimens treated with the triorganotin(IV) complexes, structural damages such as 'achromatic lesions' and 'chromosome breakages' have been identified.

Considerable attention has been given in recent years to the possibility that xenobiotics in the environment may affect reproduction in animals. In this study, the relative impact of tributyltin(IV) (TBT) chloride, one of the most toxic environmental pollutants, was investigated using Ciona intestinalis ovary as a model system. The pleiotropic effects of TBT exposure are concentration dependent and include a decrease of ATP levels, lipid content and nucleic acid content and synthesis. In contrast, a marked increase in calcium (Ca2+) and glucose content is observed. Furthermore, TBT alters enzymatic activity, inhibiting creatine kinase and stimulating alkaline phosphatase and cholinesterase (at concentrations higher than 10−5M in sterile sea water solution). The implications of these effects on reproduction and embryonal development are discussed, along with the possibility that they reflect an extreme cellular defence mechanism triggered to avoid deleterious consequences for the survival of the species.Copyright © 2001 John Wiley & Sons, Ltd.

Molecules. XIV. Biological Activity of Dialkyl and Trialkyltin(IV) [Meso-tetra(4-carboxyphenyl)porphinate] Derivatives C. Mansueto, E. Puccia, F. Maggio, R. Di Stefano, T. Fiore, C. Pellerito, F. Triolo and L. Pellerito* Dipartimento di Biologia Animale, Universita di Palermo, Via Archirafi 18, 90123 Palermo, Italy Dipartimento di Chimica Inorganica, Universita di Palermo, Viale delle Scienze, Parco d’Orleans, 90128 Palermo, Italy

Several complexes of R n SnCl 4-n (R = Me, Ph, n = 1-3; R = nBu, n = 2, 3) with phosphocholine and dimyristoyl-L-α-phosphatidylcholine (phospholipid) have been synthesized and characterized by means of Mossbauer spectroscopy and NMR. Triorganotin chlorides form complexes of (R 3 SnCl) 2 .L stoichiometry with a trigonal bipyramidal pentacoordinate tin environment, while the others form 1:1 complexes with an octahedral hexacoordinate tin environment, with the ligands coordinating through anionic phosphodiester moieties in all cases.

Dialkyltin(IV) and trialkyltin(IV) derivatives of the coenzyme thiaminepyrophosphate (H2TPP) have been synthesized with general formula R2Sn(HTPP)2·nH2O (Alk = Me, n = 2; Alk = Bu, n = 4) and R3SnHTPP·nH2O (R=Me, n = 2; R = Bu, n = 1), respectively. The solid-state structure of the complexes has been investigated through infrared and Mossbauer spectroscopy. The infrared data suggest the involvement of only phosphate oxygen atoms in the coordination of both dialkyl- and trialkyl-tin(IV) moieties, with phosphate anions behaving as monoanionic bidentate bridging or chelating groups, with the tin(IV) involved in six- and five-fold coordination geometries, respectively, in R2Sn(HTPP)2·nH2O (R = Me, n = 2; R = Bu, n = 4) and R3SnHTPP·nH2O (R = Me, n = 2; R = Bu, n = 1). The 119Sn Mossbauer data, and in particular rationalization of the experimental nuclear quadrupole splittings, Δ, through the point-charge model formalism, suggests the occurrence of an octahedral trans-R2 structure in R2Sn(HTPP)2·nH2O (R = Me, n = 2; R = Bu, n = 4) and a trigonal-bipyramidal structure in R3SnHTPP·nH2O (R = Me, n = 2; R = Bu, n = 1). 1H and 13C NMR spectra, in D2O, suggested that the soluble derivatives, at room temperature, in solution, maintained the solid-state structure. The interactions of dibutyltin(IV)–thiaminepyrophosphate (DBTPP) and tributyltin(IV)–thiaminepyrophosphate (TBTPP) complexes with Bluescript KS(+) plasmid and immortalized 3T3 fibroblasts were studied. Both compounds have a clear inhibitory effect on the growth of immortalized mouse embryonal fibroblasts (NIH-3T3), TBTPP being the much more active. No evidence was found, however, for DNA cleavage by the compounds at molar ratios as high as 1:10 (DBTPP, TBTPP/DNA base pairs). According to our observations, the cytotoxicity of TBTPP does not seem to be based on direct interaction with DNA, but in the presence of TBTPP (1:10, TBTPP/DNA bp), plasmid DNA seems to be more susceptible to cleavage by UV. Copyright © 1999 John Wiley & Sons, Ltd.

The cytotoxic derivatives diorganotin(IV) and triorganotin(IV) [meso-tetra(4-carboxyphenyl)porphinates, with stoichiometries [R2Sn]2TPPC and [R3Sn]4TPPC [R = Me, Bu, Ph; TPPC4−­= meso-tetra(4-carboxyphenyl)porphinate4−], namely bis[dimethyltin(IV)], bis[dibutyltin(IV)], bis[diphenyltin(IV)], tetra[trimethyltin(IV)], tetra[tributyltin(IV)] and tetra[triphenyltin(IV)] [meso-tetra(4-carboxyphenyl)porphinate]s, have been used to investigate their effects on the cultured human kidney cell cycle in order to understand further the origin of cell-growth inhibition induced by the above-mentioned chemicals. The cell-cycle-dependent DNA content distribution of cultured cells exposed to these compounds has been analyzed through flow cytometry, a potent technique capable of probing several aspects of drug-induced cytotoxicity. Cultured human kidney cells have been used as a model system, on the premise of greater physiological similarity to the human situation in vivo. Copyright © 1999 John Wiley & Sons, Ltd.

Amphiphilic cyclodextrin (ACyD) provides water-soluble and adaptable nanovectors by modulating the balance between the hydrophobic and hydrophilic chains at both CyD sides. This work aimed to design nanoassemblies based on nonionic and hydrophilic ACyD (SC6OH) for the delivery of a poor-water-soluble organotin(IV)-porphyrin derivative [(Bu3Sn)4TPPS] to melanoma cancer cells. To characterize the porphyrin derivatives under simulated physiological conditions, a speciation was performed using complementary techniques. In aqueous solution (≤ 20 μM), (Bu3Sn)4TPPS primarily exists as a monomer (2 in Figure 1), as suggested by the low static anisotropy (ρ ≈ 0.02) with a negligible formation of porphyrin supramolecular aggregates. MALDI-TOF spectra indicate the presence of moieties (i.e., [(Bu3Sn)3TPPS](-)) that are derivatives of the monomeric species. Spectrofluorimetry coupled with potentiometric measurements primarily assesses the presence of the hydrolytic [(Bu3Sn)4TPPS (OH)4](4-) species under physiological conditions. Nanoassemblies of (Bu3Sn)4TPPS/SC6OH were prepared by dispersion of organic films in PBS at pH 7.4 and were investigated using a combination of spectroscopic and morphological techniques. The UV-vis and emission fluorescence spectra of the (Bu3Sn)4TPPS/SC6OH reveal shifts in the peculiar bands of the organotin(IV)-porphyrin derivative due to its interaction with the ACyD supramolecular assemblies in aqueous solution. The mean size was within the range of 100-120 nm. The ξ-potential was negative (-16 mV) for the (Bu3Sn)4TPPS/SC6OH nanoassemblies, with an entrapment efficiency of approximately 67%. The intracellular delivery, cytotoxicity, nuclear morphology and cell growth kinetics were evaluated via fluorescence microscopy on A375 human melanoma cells. The delivery of (Bu3Sn)4TPPS by ACyD with respect to free (Bu3Sn)4TPPS increases the internalization efficiency and cytotoxicity to induce apoptotic cell death and, at lower concentrations, changes the cellular morphology and prevents cell proliferation.

Three new triorganotin(IV) complexes of valproic acid (vp1, Me3Sn-valproate; vp2, Bu3Sn-valproate; vp3, Ph3Sn-valproate) have been synthesized and investigated by spectroscopic and biological methods. An anionic, monodentate valproate ligand was observed, ester-like coordinating the tin atom on a tetra-coordinated, monomeric environment. The structures, though, can distort towards a penta-coordination, as a consequence of a long range O center dot center dot center dot Sn interaction. Crystallographic and NMR findings confirm this situation both in solid state and solution. Biological finding evidenced a clear cytotoxic action of the complexes in hepatocellular carcinoma cell cultures: one of the complexes induced an 80% cell viability reduction after 24 h treatment in HepG2 cells. This effect was accompanied by the appearance of biochemical signs of apoptosis. In Chang liver cells, the same compound induced only modest effects, suggesting a potential use as anti-cancer drug. Preliminary evaluations on hyperacetylation state of histone H3 in tributyltin-valproate treated HepG2 cells showed an increase in Ac-H3 (histone H3 acetylated at lys-9 and lys-14), suggesting that the compound maintains the deacetylation inhibition activity of its ligand valproate. (c) 2013 Elsevier Inc. All rights reserved.

In previous studies we have demonstrated that two derivatives of meso-Tetra(4-sulfonatophenyl)porphine (TPPS), (Bu2Sn)2TPPS and (Bu3Sn)4TPPS, cause apoptotic death of A375 melanoma cells and, at lower concentrations, arrest of cell proliferation. In the present study, we examined if the manganese metal inside the porphyrin cavity could improve the efficacy of this class of compounds. Thus, [meso- Tetra(4-sulfonatophenyl)porphine]Mn(III)Cl (=MnTPPS) derivatives, namely (Me2Sn)2MnTPPS, (Bu2Sn)2MnTPPS, (Me3Sn)4MnTPPS and (Bu3Sn)4MnTPPS, were tested on the A375 human melanoma cell line. A cytotoxicity assay showed that (Bu2Sn)2MnTPPS and (Bu3Sn)4MnTPPS were highly cytotoxic by inducing apoptosis in melanoma cells, as shown by DNA fragmentation analysis and by apoptotic nuclei fluorescence, and when used at lower concentrations, they affected only cellular proliferation. An arrest of cell proliferation was also observed with (Me3Sn)4MnTPPS, but at the highest concentrations used. Moreover, the lower concentration of (Bu3Sn)4MnTPPS induced a change in cell morphology, from a polygonal to an elongated and spindle-shaped phenotype, likewise to its cognate (Bu3Sn)4TPPS, previously tested. Western blotting analysis showed indeed that both tributyltin compounds, i.e. (Bu3Sn)4MnTPPS and (Bu3Sn)4TPPS, lowered levels of the major proteins involved in tumorigenesis: ß-catenin, c-myc and snail. We also demonstrated that all compounds entered the cells and localized in the nuclei. In conclusion, our results show that, in spite of the Mn(III) metal introduction, the butyl derivatives always have a higher efficacy than methyl derivatives, and the tributyltin compounds in particular have an interesting effect in vitro on A375 cell proliferation.

Three new complexes of Ru(II), namely [RuCl 2 (Glun-N,O) 2 ]Na 2 ( I ; Glun = glucosaminate), [RuCl 2 (1-Tglu)(EtOH) 2 ]Na ( II ; 1-Tglu = 1-thio-β- d -glucose) and [Ru 2 (EtOH) 6 (AL)Cl 4 ] ( III ; AL = 6′-aminolactose) were prepared from the same Ru(II) precursor, [RuCl 2 (DMSO) 4 ] (DMSO = dimethyl sulfoxide). The characterization of the complexes was carried out by elemental analysis, FT-IR, ES-MS, NMR, EXAFS and DFT calculations. The effectiveness of the complexes on metastatic melanoma A 375 was investigated. The results show that complex II is the most active species.

Polymers in general and metal-containing polymers in particular are often sparingly soluble or insoluble, in contrast to small molecules. Thus, special significance is attached to characterization techniques that can be applied to the materials as solids. Here, three techniques are discussed that give structural information gained from the solid material. Mossbauer spectroscopy is a powerful technique that may give information on the structure about the metal-containing moiety for about 44 different nuclei. Its use in describing the structure of the product obtained from organotin dichlorides and the unsymmetrical ciprofloxacin is presented along with the reaction implications of the results. Solid state NMR is also a useful tool in describing the structure of metal-containing polymers and its use is briefly described. Finally, MALDI MS can be used to gain structural information. For many metals it is particularly useful because of the presence of different isotopes that allow the identification of units through comparison of these isotope abundances with ion fragment clusters. Each of these tools can provide important structural characterization information.

Three new complexes of the steroid sodium fusidate (sodium 2-[(1 S ,2 S ,5 R ,6 S ,7 S ,10 S ,11 S ,13 S , 14 Z ,15 R ,17 R )-13-(acetyloxy)-5,17-dihydroxy-2,6,10,11-tetramethyl tetracyclo[8.7.0.0 2,7 .0 11,15 ] heptadecan-14-ylidene]-6-methylhept-5-enoate = (NaFusidate, Na FA )]), with triorganotin(IV) moieties have been prepared and investigated by conventional techniques as FTIR, Mossbauer, ESI-MS and NMR spectroscopy. The isolated compounds showed stoichiometries organotin(IV)/fusidate 1/1, R 3 Sn(IV) FA (R = Me, FA1 ; Bu, FA2 ; Ph, FA3 ). The ligand coordination sites were determined by FTIR spectroscopic measurements. In the complexes, the carboxylate group of the fusidate ligand behaves as monodentate monoanionic donor, binding the Sn(IV) through one oxygen atom. On the basis of C–Sn–O COO angles, calculated through the rationalization of the 119 Sn Mossbauer parameter nuclear quadrupole splitting, it has been confirmed that, in all the solid state complexes, the Sn(IV) was tetracoordinated in a distorted tetrahedral structure. Further data from 119 Sn CP-MAS spectra confirmed the distorted tetrahedral arrangement. In MeOH solution, 1 H, 13 C and 119 Sn NMR spectroscopy showed monomeric complexes, where the carboxylate group mainly acts as monodentate ester-type ligand, and the occurrence of a coordinated solvent molecule to the tin center, as validated by non-relativistic NMR DFT study.

Diorganotin(IV) complexes of N-acetyl-L-cysteine (H(2)NAC; (R)-2-acetamido-3-sulfanylpropanoic acid) have been synthesized and their solid and solution-phase structural configurations investigated by FTIR, Mössbauer, (1)H, (13)C and (119)Sn NMR spectroscopy. FTIR results suggested that in R(2)Sn(IV)NAC (R = Me, Bu, Ph) complexes NAC(2-) behaves as dianionic tridentate ligand coordinating the tin(IV) atom, through ester-type carboxylate, acetate carbonyl oxygen atom and the deprotonated thiolate group. From (119)Sn Mössbauer spectroscopy it could be inferred that the tin atom is pentacoordinated, with equatorial R(2)Sn(IV) trigonal bipyramidal configuration. In DMSO-d(6) solution, NMR spectroscopic data showed the coordination of one solvent molecule to tin atom, while the coordination mode of the ligand through the ester-type carboxylate and the deprotonated thiolate group was retained in solution. DFT (Density Functional Theory) study confirmed the proposed structures in solution phase as well as the determination of the most probable stable ring conformation. Biological investigations showed that Bu(2)SnCl(2) and NAC2 induce loss of viability in HCC cells and only moderate effects in non-tumor Chang liver cells. NAC2 showed lower cytotoxic activity than Bu(2)SnCl(2), suggesting that the binding with NAC(2-) modulates the marked cytotoxic activity exerted by Bu(2)SnCl(2). Therefore, these novel butyl derivatives could represent a new class of anticancer drugs.

Several new diorganotin(IV) and triorganotin(IV) complexes with 4-amino-3- (4-chloro phenyl)]-butanoic acid ( = Baclofen) have been synthesized and their structure investigated both in the solid state and in solution phase through spectroscopic methods (FT-IR, Mössbauer, 1H and 13C NMR). According to experimental analytical data, the stoichiometry of the complexes has been proposed as R2SnBac2 and R3SnBac, respectively for diorganotin(IV) and triorganotin(IV) baclofen complexes. (Baclofen = HBac; R = Me, Bu, Ph).

The complexation of one steroid antibiotic of the fusidane family, sodium fusidate [sodium 2-16-acetyloxy-3,11-dihydroxy-4,8,10,14-tetramethyl-2,3,4,5,6,7,9,11,12, 13,15,16-dodeca hydro-1H-cyclopenta[a]phenanthren-7-ylidene)-6-methyl-hept-5-enoate = (Nafus)], by dialkyltin(IV) has been studied by conventional technique as FT-IR, Mössbauer and NMR spectroscopies. Analytical data supported the general formula Alk2Sn(IV)fus2 (Alk = Me, Bu). Infrared spectral data of the complexes imply the presence of both uni- and bidentate, ester-type and bridging carboxylate group, respectively. On the basis of FT-IR and 119Sn Mössbauer spectroscopy, in both Me2Sn(IV)fus2 and Bu2Sn(IV)fus2, trigonal bipyramidal configurations are proposed. NMR spectra, of both ligand and of the complexes were carried in DMSO-d6 solution, in which dialkyltin(IV)bis(fusidate) maintained their solid-state configuration. In vitro antimicrobial tests were performed on complexes, and good anti-staphylococcal activity was observed.

Four new diorganotin(IV), (R = Me, Bu), and triorganotin(IV), (R = Me, Ph), derivatives of the phosphomycin disodium salt antibiotic[(1R,2S)-1,2-epoxypropylphosphonate]Na2 have been synthesized and their solid state configuration studied by X-ray crystallography, FT-IR, Mossbauer, UV–Vis spectroscopies. The X-ray diffraction investigation, performed on the bis[trimethyltin(IV)]phosphomycin, showed that the coordination geometry at all the Sn atoms is trigonal bipyramidal. The structure of the complex forms an unusual polymeric zig-zag planar network. The FT-IR and the 119Sn Mossbauer studies supported the formation of trigonal bipyramidal (Tbp) molecular structures, both in the diorganotin(IV) and triorganotin(IV) derivatives, even if, in the case of diorganotin(IV) derivatives, the tetrahedral structure cannot be a priori excluded. The PO 3 2 - group of phosphomycin coordinates the organotin(IV) centers originating a monodimensional polymeric network, as inferred by variable temperature 119Sn Mossbauer spectroscopy, used to investigate lattice dynamics of the bis-[trimethyltin(IV)]phosphomycin complex.

Organotin(IV) compounds are characterized by the presence of at least one covalent C–Sn bond. The compounds contain tetravalent {Sn} centers and are classified as mono-, di-, tri-, and tetraorganotin(IV), depending on the number of alkyl (R) or aryl (Ar) moieties bound. The anions are usually Cl, F, O2, OH,–COO, or –S. It seems that the nature of the anionic group has only secondary importance in biological activity. The rapid rise in the industrial (catalyst in PVC and foam production), agricultural (fungicides and acaricides), and biological applications (wood, stone, and glass preservatives) of organotin(IV) compounds during the last few decades has led to their accumulation in the environment and, consequently, in biological systems. It is well known that organotin(IV) compounds display strong biological activity. Most organotin(IV) compounds are generally very toxic, even at low concentration. The biological activity is essentially determined by the number and nature of the organic groups bound to the central {Sn} atom. The [R3Sn(IV)]+ and [Ar3Sn(IV)]+ derivatives exert powerful toxic action on the central nervous system. Within the series of [R3Sn(IV)]+ compounds, the lower homologs (Me, Et) are the most toxic when administrated orally, and the toxicity decreases progressively from propyl (Pr) to octyl (Oc), the latter being not toxic at all towards humans.