Synthesis and characterization of water-insoluble and water-soluble dibutyltin(IV) porphinate complexes based on the tris(pyridinyl)porphyrin moiety,their anti-tumor activity in vitro and interaction with DNA

The water-insoluble and water-soluble organotin(IV)porphinate complexes based on the tris-(4-pyridinyl)porphyrin and tris(N-methyl-4-pyridiniumyl)porphyrin moieties were synthesized and characterized by elemental analysis, (1)H NMR, IR and electrospray ionization mass spectra. The in vitro activity of the compounds against P388 leukemia and A-549 was determined. The results show that the anti-tumor activities of organotin(IV)porphinate is related to the water solubility of the compounds and the central ion in the porphyrin ring. The interaction between the water-soluble dibutyltin(IV) porphinate (7 and 10) complexes and DNA has been investigated. The result shows that compounds 7 and 10 cause DNA hypochromism measured by A(260), a slight increase in the viscosity of the DNA, and an increase in the melting point of DNA by 2.9 and 1.6 degrees C, respectively at DNA(base)/Drug(Por) ratios of 60. The binding constants to DNA were 1.35+/-0.16 x 10(7) M(-1) (7) and 1.45+/-0.12 x 10(6) M(-1) (10) determined using EB competition method based on the porphyrin concentration, which is 20 and five times greater than that of precursor porphyrins [5-p,o-(carboxy)methoxyphenyl-10,15,20-tris(N-methyl-4-pyridiniumyl)] porphyrin (p,o-tMPyPac) to DNA. Electrophoresis test shows that the compounds cannot cleave the DNA. According to the electrophoresis test result and all the above results, the cytotoxic activity against P388 and A-549 tumor cells appears not to come from the cleavage of DNA caused by the compounds but from the high affinity of compounds to DNA.     

Organotin compounds induce aneuploidy in human peripheral lymphocytes in vitro

In vitro exposure of PHA-stimulated human lymphocytes to organotin compounds resulted in statistically significant increases in the frequencies of hyperdiploid cells. When taken together with our previous study demonstrating spindle inhibiting effects of the same organotin compounds by an indirect method (Jensen et al., 1989), the present study strongly indicates that organotin compounds are able to induce aneuploidy, probably by affecting spindle function.     

Sulfamic and succinic acid derivatives of 25-OH-PPD and their activities to MCF-7, A-549, HCT-116, and BGC-823 cell lines

In the search for new anti-tumor agents with higher potency than our previously identified compound 1 (25-OH-PPD, 25-hydroxyprotopanaxadiol), 12 novel sulfamic and succinic acid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 1, compounds 2, 3, and 7 exhibited higher cytotoxic activity on A-549 and BGC-823 cell lines, together with lower toxicity in the normal cell. In particular, compound 2 exhibited the best anti-tumor activity in the in vitro assays, which may provide valuable data for the research and development of new anti-tumor agents.     

Synthesis, structure, antimicrobial, and genotoxic activities of organotin compounds with 2,6-diacetylpyridine nicotinoyl- and isonicotinoylhydrazones.

A series of organotin compounds obtained from the reaction of 2,6-diacetylpyridine nicotinoyl- and isonicotinoylhydrazones with tri- and diorganotin chlorides was investigated. The IR and 119Sn NMR spectroscopic characterization of all the compounds is reported, together with the x-ray crystal structure of [SnEt2(H2dapin')]2[SnEt2Cl3]Cl3.2H2O (H2dapin' = 2,6-diacetylpyridine bis(isonicotinoylhydrazone)). The main feature in this compound is the presence of a tin atom in both the complex ionic units. The coordination polyhedron is a pentagonal bipyramid in the cation and a trigonal bipyramid in the anion. Results are discussed concerning the in vitro evaluation of antimicrobial properties and genotoxic potential of the compounds described. In all cases the complexes show a reduced antimicrobial activity as compared to that of the corresponding organotin compound. Genotoxic properties of the ligands, detected in the Ames test, disappear in the complexes.     

Toxicity and speciation analysis of organotin compounds

Abstract

The use of antifouling paints in shipbuilding has led to a significant concentration of organotin compounds in the marine environment. Antifouling paints have become the main source of tributyltin and triphenyltin derivatives loaded into the sea. The toxicity of organotin compounds has been of great concern. High concentrations of organotin compounds are associated with growth abnormalities in mussels and oysters and have also resulted to the decline in their abundance. High concentration of organotin compounds have also been found in the tissues of marine mammals and its presence has been linked to mass mortalities of marine mammals. It causes imposex and calcification anomalities in mollusks. Seafood is thought to be a possible source of organotin compounds in human. Therefore, to evaluate the environmental distribution and fate of these compounds and to determine the effectives of legal provisions adopted by a number of countries, a variety of analytical methods have been developed for the speciation of organotin compounds in the environment. A detailed review of the toxicity and chemical speciation of organotin compounds is given.     

Inhibition of oxidative phosphorylation by organotin thiocarbamates

A series of triphenyl-, tricyclohexyl- and tribenzyltin compounds have been synthesized and examined as inhibitors of mitochondrial oxidative phosphorylation. All compounds tested inhibit oxidative phosphorylation linked to succinate oxidation by potato tuber mitochondria. All of the organotin compounds inhibit ADP-stimulated O2 uptake linked to succinate oxidation with concentrations for 50% inhibition in the range 2-50 microM. This inhibition is not due to inhibition of electron transport from succinate to O2 per se: none of the organotin compounds at 50 microM substantially inhibit the rate of succinate oxidation in the presence of 2,4-dinitrophenol. Representative organotin compounds at 0.5-50 microM do not act as uncouplers of succinate oxidation. It is concluded that the organotin compounds act as energy transfer inhibitors to inhibit oxidative phosphorylation in potato tuber mitochondria. A similar mode of action of representative organotin compounds was found with rat liver mitochondria. These organotin compounds inhibit a hydrophobic Ca2+-dependent plant protein kinase in the absence but not in the presence of thiols.     

Organotin and osmoregulation: quantifying the effects of environmental concentrations of sediment-associated TBT and TPhT on the freshwater-adapted European flounder, Platichthys flesus (L.)

Chronic (5 weeks) exposure of freshwater-adapted European flounder, Platichthys flesus (L.), to environmental concentrations of sediment-associated tri-n-butyltin chloride (TBTCl) and triphenyltin chloride (TPhTCl) caused significant changes to hydromineral fluxes and membrane permeability, mechanisms that maintain osmotic homeostasis. The half-time of exchange of tritiated water (THO) in TBTCl- and TPhTCl-exposed fish was significantly increased during the first 2 weeks of the experiment and then decreased steadily, eventually reaching the level that the control group had constantly maintained throughout the experiment. This change in apparent water permeability was accompanied by a significant decrease in diffusional water flux across the membranes. Passive Na(+)-efflux across the gills was increased significantly but effluxes in the control group were near constant over the same time span. Drinking rates in the organotin groups increased significantly while the rate of urine production did not change. This lead to an increased net water balance in the organotin groups and consequently to a significant reduction of the blood osmolality of both organotin groups when compared to a control. There would appear to be a metabolic cost attached to the changes produced by exposure to environmental levels of organotin compounds which are manifested as a minimal increase in body length compared to the controls.     

Interaction of tributyltin(IV) chloride and a related complex [Bu(3)Sn(LSM)] with rat leukocytes and erythrocytes: Effect on DNA and on plasma membrane

The discovery of the antitumor activity of cisplatin led several research groups to investigate the possible therapeutic applications of other metal-based compounds. Organotin(IV) complexes have been developed from organotin compounds that were employed in industry and agriculture as stabilizers and pesticides, respectively. A careful choice of the ligand coordinated to an organotin(IV) fragment can modulate the activity of the organotin(IV) complex and minimize its drawbacks. With this aim, the tributyltin(IV) complex [Bu(3)Sn(LSM)] (LSM=bis(1-methyl-1H-imidazol-2-ylthio)acetate) was synthesized and its in vitro effects on rat blood cells were compared with those of the analogous tributyltin(IV) compound without the anionic ligand. Comet-assay results show that both the tributyltin(IV) chloride (TBTC) and the complex [Bu(3)Sn(LSM)] can induce DNA damage in leukocytes, but a stronger effect was observed in the presence of the organotin(IV) complex. Moreover, lipid-hydroperoxide formation in leukocyte plasma membranes increases more in the presence of [Bu(3)Sn(LSM)] compared with TBTC, while TBTC can change the lipid order and packing of leukocytes and, partially, erythrocyte plasma membranes. The treatment of whole blood with these two compounds shows a preferential oxidative effect of TBTC on erythrocyte plasma membranes and erythrocyte oxidative processes, which influence the induction of DNA damage in leukocytes. The different hydrophobic characters and the different extents of steric hindrance of TBTC and [Bu(3)Sn(LSM)] influence the capacity of the two compounds to cross the plasma membrane and affect the pathways that lead to DNA damage.     

Effect of organotins on fecal pollution indicator organisms.

Pure cultures of Escherichia coli and Streptococcus faecalis and environmental water samples were examined for the possibility that pollution involving organotin compounds could decrease the values for indicator organisms when standard methods were applied to the analysis of water samples. (CH3)2SnCl2 and (CH3)3SnCl decreased viable counts at about 10 to 100 mg of Sn liter-1 (8.4 X 10(-5) to 8.4 X 10(-4) mol of Sn liter-1), and tributyltin chloride was effective at about 0.1 to 1.0 mg of Sn liter-1 (8.4 X 10(-7) to 8.4 X 10(-6) mol of Sn liter-1. These concentrations, particularly for the methyltin compounds, are greater than the concentrations reported to date for these compounds in aquatic ecosystems. Thus, organotin compounds alone would not be likely to cause reductions in counts of indicator organisms measured by standard methods. However, it is suggested that, when combined with other environmental stressors or upon long exposure, organotins such as butyltins may contribute to the injury of indicator organisms.     

Effect of organotins on fecal pollution indicator organisms

Pure cultures of Escherichia coli and Streptococcus faecalis and environmental water samples were examined for the possibility that pollution involving organotin compounds could decrease the values for indicator organisms when standard methods were applied to the analysis of water samples. (CH3)2SnCl2 and (CH3)3SnCl decreased viable counts at about 10 to 100 mg of Sn liter-1 (8.4 X 10(-5) to 8.4 X 10(-4) mol of Sn liter-1), and tributyltin chloride was effective at about 0.1 to 1.0 mg of Sn liter-1 (8.4 X 10(-7) to 8.4 X 10(-6) mol of Sn liter-1. These concentrations, particularly for the methyltin compounds, are greater than the concentrations reported to date for these compounds in aquatic ecosystems. Thus, organotin compounds alone would not be likely to cause reductions in counts of indicator organisms measured by standard methods. However, it is suggested that, when combined with other environmental stressors or upon long exposure, organotins such as butyltins may contribute to the injury of indicator organisms.     

Synthesis and anti-angiogenic activity of 6-(1,2,4-thiadiazol-5-yl)-3-amino pyridazine derivatives

General screening for inhibitors of microvessel growth in vitro in the rat aortic ring assay led to the discovery of a novel series of thiadiazole pyridazine compounds with potential anti-angiogenic activity. Chemical optimization produced orally active compounds with potent in vitro and in vivo anti-angiogenesis and anti-tumor activities.     

Construction and assessment of reaction models between F1F0-synthase and organotin compounds: molecular docking and quantum calculations

Organotin compounds are the active components of some fungicides, which are potential inhibitors of the F₁F₀-ATP synthase. The studies about the reaction mechanism might indicate a pathway to understand how these compounds work in biological systems, however, has not been clarified so far. In this line, molecular modeling studies and density functional theory calculations were performed in order to understand the molecular behavior of those compounds when they interact with the active site of the enzyme. Our findings indicate that a strong interaction with His132 can favor a chemical reaction with organotin compounds due to π–π stacking interactions with aromatic rings of organotin compounds. Furthermore, dependence on molecule size is related to possibility of reaction with the amino acid residue His132. Thus, it can also be noticed, for organotin compounds, that substituents with four carbons work by blocking the subunit a, in view of the high energy transition found characterized by steric hindrance.     

Synthesis and cytotoxic activity of 17-carboxylic acid modified 23-hydroxy betulinic acid ester derivatives

New 17-carboxylic acid modified 23-hydroxy betulinic acid ester derivatives were prepared and tested for cytotoxic activity on five cancer cell lines in vitro: all tested compounds showed stronger cytotoxic activity than 23-hydroxy betulinic acid and betulinic acid. In addition, compound 5a was tested for anti-tumor activity in vivo: it had much better anti-tumor activity than 23-OH betulinic acid and had similar anti-tumor activity with cyclophosphamide and 5-fluorouracil.     

Templating ��-amylase peptide inhibitors with organotin compounds

Metal centers have been widely used to nucleate secondary structures in linear peptides. However, very few examples have been reported for peptide/organometal complexes. Here, we illustrate the use of organotin compounds as nucleation centers for secondary structures of linear peptide inhibitors of ??-amylase. Specifically, we utilized methyl-substituted tin compounds to template short type I ??-turns similar to the binding loop of tendamistat, the natural inhibitor of the enzyme, which are able to bind and inhibit ??-amylase. We show that enzyme activity is inhibited by neither the unstructured peptide nor the organotin compounds, but rather the peptide/organotin complex, which inhibits the enzyme with K _i?~?0.5???M. The results delineate a strategy to use organometallic compounds to drive the active conformation in small linear peptides.     

Design and synthesis of novel Gefitinib analogues with improved anti-tumor activity

There is an urgent need to design and develop new and more potent EGFR inhibitors with improved anti-tumor activity. Here we describe the design and synthesis of two series of 4-benzothienyl amino quinazolines as new analogues of the EGFR inhibitor Gefitinib. The anti-tumor activity of these novel Gefitinib analogues in 6 human cancer cell lines was examined. Compared with the parental Gefitinib, most of the new compounds show a markedly increased cytotoxicity to cancer cells. Furthermore, several of the series B compounds that side chains at position 7 contain either a methyl or ethyl group are potent pan-RTK inhibitors. Two representative compounds in this class, 15 and 17, have an enhanced capability to inhibit cancer cell growth and induce apoptosis in vitro and inhibit tumor formation in vivo in human cancer cells with high HER-2, as compared with the parental Gefitinib. Thus they may be promising lead compounds to be developed as an alternative for current Gefitinib therapy or for Gefitinb-resistant patients, potentially via simultaneously blocking multiple RTK signaling pathways.     

肉桂油成分分析及肉桂醛体外抗肿瘤活性研究

目的探讨肉桂醛对不同肿瘤细胞株的生长抑制作用。方法通过水蒸气蒸馏法提取肉桂油,用气相色谱—质谱联用仪进行肉桂油成分分析;采用噻唑蓝（MTT）比色法检测肉桂醛对体外培养的人宫颈癌细胞系HeLa细胞株、人肺癌细胞系A-549细胞株和人肝癌细胞系HepG2细胞株的生长抑制作用,计算半数抑制浓度（IC50）。结果肉桂油的收率为1.96%,分析了肉桂油中的10种成分,主要为肉桂醛,占总馏出峰面积的93.94%;肉桂醛能抑制人宫颈癌细胞系HeLa细胞、人肺癌细胞系A-549细胞和人肝癌细胞系HepG2细胞增殖,且呈剂量依赖性,IC50值分为0.20、0.36和0.73 mg/mL。结论肉桂醛具有体外抗肿瘤活性。     

Organotin compounds and their interactions with microorganisms.

Organotin compounds are ubiquitous in the environment. The general order of toxicity to microorganisms increases with the number and chain length of organic groups bonded to the tin atom. Tetraorganotins and inorganic tin have little toxicity. Because of their lipophilicity, organotins are regarded as membrane active. There is evidence that the site of action of organotins may be both at the cytoplasmic membrane and intracellular level. Consequently, it is not known whether cell surface adsorption or accumulation within the cell, or both is a prerequisite for toxicity. Biosorption studies on a fungus, cyanobacteria, and microalgae indicates that cell surface binding alone occurred in these organisms, while studies on the effects of TBT (tributyltin) on certain microbial enzymes indicated that in some bacteria TBT can interact with cytosolic enzymes. Microorganism-organotin interactions are influenced by environmental conditions. In aquatic systems, both pH and salinity can determine organotin speciation and therefore reactivity. These environmental factors may also alter selectivity for resistant microorganisms in polluted systems. Tin-resistant microorganisms have been identified, and resistance can be either plasmid or chromosomally mediated. In one TBT-resistant organism, an Altermonas sp., an efflux system was suggested as the resistance mechanism. Biotransformation of organotin compounds by debutylation or methylation has been observed. These reactions may influence the toxicity, mobility, and environmental fate of organotin compounds.     

The Speciation of Organotin Compounds in Sediment and Water Samples from the Port of Gdynia

Organotin compounds (OTC) are toxic towards all living organisms. The application of organitin-based antifouling systems is becoming the main source of OTC in the ocean. Harbor sediments and water contain large deposits of organotin compounds due to application of antifouling systems in the shipping industry. OTC contamination presents a potential risk to the marine environment.

Sediment and water samples were collected in 2009 from Gdynia Harbor. For all the analyzed organotin compounds, the mean concentration values were determined: water samples monobutyltin (MBT): 13.2, dibutyltin (DBT): 16.7, tributyltin (TBT): 60.7 (ng cation dm^?3), and sediment samples MBT: 261.4, DBT: 751.9, TBT: 2148.2 (ng cation g^?1 d.w.). The estimated content of monophenyltin (MPhT), diphenyltin (DPhT), triphenyltin (TPhT), monooctyltin (MOT), dioctyltin (DOT), and tricyclohexyltin (TCHT) were below the detection limit of the applied method. It was found that the content of organic matter, the amount of fine fraction, and the pH all play a significant role in the distribution and sorption process of OTC between the water and the sediment on the bottom. Compared to an earlier study, the concentrations of all OTC are much lower, confirming that the applied legislation has had a positive impact.     

Organotin-induced hemolysis,shape transformation and intramembranous aggregates in human erythrocytes

Organotin compounds examined in this study exhibited a relative order of potency for induction of in vitro hemolysis in human erythrocytes as follows: tri-n-butyltin > tri-n propyltin > tetra-n-butyltin > triphenyltin chloride > tri-n-ethyltin bromide > dibutyltin dichloride > stannous chloride > tri-n-methyltin chloride = butyltin chloride dihydroxide. All of the organotin compounds induced erythrocyte shape transformation from the normal discocyte to an echinocyte and, in addition, triphenyltin chloride, tetra-n-butyltin and tri-n-ethyltin bromide also elicited stomatocyte formation at higher concentrations. Select organotin compounds also formed tin-containing aggregates within the plasma membrane. The relative order of effectiveness for organotin induction of intramembranous aggregates was tri-n-butyltin > tri-npropyltin > tetra-n-butyltin > tri-n-ethyltin bromide, which was based upon the lowest concentration at which they were observed. These results support the previously suggested theory that organotins are membrane effectors because of their comparatively high hydrophobic, lipid partitioning properties. The relatively lipophilic compound, triphenyltin chloride, appeared to be anomalous because it did not readily promote hemolysis or induce the formation of intramembranous aggregates in human erythrocytes. A log-linear statistical model demonstrated an association of hemolysis with both tri-n-butyltin aggregate formation and shape transformation. Select organotin compounds should be useful probes in membrane studies because of their numerous effects.Abbreviations DBT dibutylin dichloride - MBT butyltinchloride dihydroxide - SnCl₂ stannous chloride - TBT tri-n-butyltin - TET tri-n-ethyltin bromide - TMT tri-n-methyltin chloride - TPhT triphenyltin chloride - TPT tri-n-propyltin - TTBT tetra-n-butyltin     

几种中药及其有效成分对人体肿瘤细胞增殖的抑制作用

通过建立的抗肿瘤体外模型,对临床上有抗肿瘤作用的几种中药提取物的抗肿瘤的活性进行检测。并与其中用作标准品的化学成分的活性进行比较。结果发现所检测的中药牛蒡子、蛇床子、三七、大黄、茯苓、延胡索、川乌和黄芪等的水提物和醇提物对肿瘤细胞株均有一定的抑制作用,醇提物的活性明显高于水挺物。一部分用作标准品的化学成分也有抗肿瘤活性。这项工作为抗肿瘤活性成分的筛选建立了有效的方法和基础。