Dose- and sex-related carcinogenesis by N-bis(2-hydroxypropyl)nitrosamine in Wistar rats

An initiation-promotion medium-term bioassay for detection of chemical carcinogens, developed in the male F344 rat, uses 0.1% N-bis(2-hydroxypropyl)nitrosamine (DHPN) among five genotoxic chemicals for the initiation of carcinogenesis in multiple organs. To establish this bioassay in the Wistar strain, the effects of two dose levels of DHPN were evaluated on the main DHPN rat target organs: lung, thyroid gland, kidneys and liver. Four groups of male and female animals were studied: Control--untreated group; Multi-organ initiated group (also referred to as DMBDD, based on the initials of the five initiators)-treated sequentially with N-diethylnitrosamine (DEN, i.p.), N-methyl-N-nitrosourea (MNU, i.p.), N-butyl-N-(4-hydroxy butyl)nitrosamine (BBN, drinking water), N, N'-dimethylhydrazine (DMH, s.c.) and DHPN (drinking water) for 4 weeks; a third group treated with 0.1% DHPN in drinking water for 2 weeks and the last group treated with 0.2% DHPN in drinking water for 4 weeks. The animals were sacrificed after 30 weeks. DHPN at 0.2% induced preneoplasia in the liver and kidneys of rats of both sexes, the number and area of the putative preneoplastic liver glutathione S-transferase-positive hepatocyte foci being significantly increased in these animals. It also induced benign and malignant tumors in female and in male rats. However, there was no relationship between the increased incidence of preneoplastic lesions and tumor development in the 0.2% DHPN-exposed groups of both sexes. DHPN at 0.1% induced only a few preneoplastic lesions in the liver and kidney and no tumors in both male and female rats. A clear dose and sex-related carcinogenic activity of DHPN was registered, although Wistar rats of both sexes showed a relative resistance to the carcinogenic activity of this compound.

Cyclometalated complexes derived from calix[4] arene bisphosphites and their catalytic applications in cross-coupling reactions

Palladium and platinum dichloride complexes of a series of symmetrically and unsymmetrically substituted 25,26;27,28-dibridged p-tert-butyl-calix[4]arene bisphosphites in which two proximal phenolic oxygen atoms of p-tert-butyl-or p-H-calix[4]arene are connected to a P(OR) ( R = substituted phenyl) moiety have been synthesized. The palladium dichloride complexes of calix[4]arene bisphosphites bearing sterically bulky aryl substituents undergo cyclometalation by C-C or C-H bond scission. An example of cycloplatinated complex is also reported. The complexes have been characterized by NMR spectroscopic and single crystal X-ray diffraction studies. During crystallization of the palladium dichloride complex of a symmetrically substituted calix[4]arene bisphosphite in dichloromethane, insertion of oxygen occurs into the Pd-P bond to give a P,O-coordinated palladium dichloride complex. The calix[4]arene framework in these bisphosphites and their metal complexes adopt distorted cone conformation; the cone conformation is more flattened in the metal complexes than in the free calix[4]arene bisphosphites. Some of these cyclometalated complexes proved to be active catalysts for Heck and Suzuki C-C cross-coupling reactions but, on an average, the yields are only modest. (C) 2011 Elsevier B.V. All rights reserved.

Air oxygenation chemistry of 4-TBC catalyzed by chloro bridged dinuclear copper(II) complexes of pyrazole based tridentate ligands: synthesis, structure, magnetic and computational studies

Four dinuclear bis(mu-Cl) bridged copper(II) complexes, Cu-2(mu-Cl)(2)(L-X)(2)](ClO4)(2) (L-X = N,N-bis(3,5-dimethylpyrazole-1-yl)-methyl]benzylamine with X = H(1), OMe(2), Me(3) and Cl(4)), have been synthesized and characterized by the single crystal X-ray diffraction method. In these complexes, each copper(II) center is penta-coordinated with square-pyramidal geometry. In addition to the tridentate L-X ligand, a chloride ion occupies the last position of the square plane. This chloride ion is also bonded to the neighboring Cu(II) site in its axial position forming an SP-I dinuclear Cu(II) unit that exhibits small intramolecular ferromagnetic interactions and supported by DFT calculations. The complexes 1-3 exhibit methylmonooxygenase (pMMO) behaviour and oxidise 4-tert-butylcatechol (4-TBCH2) with molecular oxygen in MeOH or MeCN to 4-tert-butyl-benzoquinone (4-TBQ), 5-methoxy-4-tert-butyl-benzoquinone (5-MeO-4-TBQ) as the major products along with 6,6'-Bu-t-biphenyl-3,4,3',4'-tetraol and others as minor products. These are further confirmed by ESI- and FAB-mass analyses. A tentative catalytic cycle has been framed based on the mass spectral analysis of the products and DFT calculations on individual intermediates that are energetically feasible.

Molecular structures and antiproliferative activity of side-chain saturated and homologated analogs of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone

Side chain homologated derivatives of 2-chloro-3-(n-alkylamino)-1,4-naphthoquinone {n-alkyl: pentyl; L-5, hexyl; L-6, heptyl; L-7 and octyl; L-8} have been synthesized and characterized by elemental analysis, FT-IR, H-1 NMR, UV-visible spectroscopy and LC-MS. Compounds, L-4, n-alkyl: butyl; L-4}, L-6 and L-8 have been characterized by single crystal X-ray diffraction studies. The single crystal X-ray structures reveal that L-4 and L-8 crystallizes in P2(1) space group, while L-6 in P2(1)/c space group. Molecules of L-4 and L-8 from polymeric chains through C-H center dot center dot center dot O and N-H center dot center dot center dot O close contacts. L-6 is a dimer formed by N-H center dot center dot center dot O interaction. Slipped pi-pi stacking interactions are observed between quinonoid and benzenoid rings of L-4 and L-8. Orientations of alkyl group in L-4 and L-8 is on same side of the chain and polymeric chains run opposite to one another to form zip like structure to the alkyl groups. Antiproliferative activities of L-1 to L-8{n-alkyl: methyl; L-1, ethyl; L-2, propyl; L-3 and butyl; L-4} were studied in cancer cells of colon (COLO205), brain (U87MG) and pancreas (MIAPaCa2) where L-1, L-2 and L-3 were active in MIAPaCa2 (L-1 = 1-2 > L-3) and COLO205 (L-2 = L-3 > L-1) and inactive in U87MG. From antiproliferative studies with compounds L-1 to L-8 it can be concluded that homologation of 2-chloro-3-(n-alkylamino)-1,4-napthoquinone with saturated methyl groups yielded tissue specific compounds such as L-2 (for MIAPaCa2) and L-3 (for COLO205) with optimal activity. (c) 2013 Elsevier B.V. All rights reserved.

Effects of sample solvent composition and injection volume on chromatographic peak profiles of methyl w- benzimidazolecarbamate and 3-butyl1-2,4-dioxo[1,2-a]-s- triazinobenzimidazole in RP-HPLC

The effects of sample solvent composition and the injection volume, on the chromatographic peak profiles of two carbamate derivatives, methyl 2-benzimidazolecarbamate (MBC) and 3-butyl-2,4-dioxo[1,2-a]-s-triazinobenzimidazole (STB), were studied using reverse phase high performance liquid chromatograph. The study examined the effects of acetonitrile percentage in the sample solvent from 5 to 50%, effects of methanol percentage from 5 to 50%, effects of pH increase from 4.42 to 9.10, and effect of increasing buffer concentration from ° to 0.12M. The effects were studied at constant and increasing injection mass and at four injection volumes of 10, 50, 100 and 200 uL. The study demonstrated that the amount and the type of the organic solvents, the pH, and the buffer strength of the sample solution can have a pronounced effect on the peak heights, peak widths, and retention times of compounds analysed. MBC, which is capable of intramolecular hydrogen bonding and has no tendency to ionize, showed a predictable increase .in band broadening and a decrease in retention times at higher eluting strengths of the sample solvent. STB, which has a tendency to ionize or to strongly interact with the sample solvent, was influenced in various ways by the changes in ths sample solvent composition. The sample solvent effects became more pronounced as the injection volume increased and as the percentage of organic solvent in the sample solution became greater. The peak height increases for STB at increasing buffer concentrations became much more pronounced at higher analyte concentrations. It was shown that the widely accepted procedure of dissolving samples in the mobile phase does not yield the most efficient chromatograms. For that reason samples should be dissolved in the solutions with higher aqueous content than that of the mobile phase whenever possible. The results strongly recommend that all the samples and standards, regardless whether the standards are external or internal, be analysed at a constant sample composition and a constant injection volume.

6-Alkyl-3,4-dihydro-2H-pyrans: Chemical Secretion Compounds in Neotropical Harvestmen

The defensive, secretions, of five neotropical) species of harvestmen, (Opiliones: Gonyleptidae) from the Brazilian Atlantic Forest were analyzed and chemically characterized by GC-MS and NMR Methods. Three of the species, Cobania picea, Roweria virescens, and Serracutisoma proximum, secrete a mixture of 2,3-dimethyl-1,4-benzoquinone and 2-ethyl-3methyl-1,4,4-benzoquinone. The secretions produced,by the Other two species Iporangaia pustulosa and Neosadocus maximus, contain 1-hepten-3-one, 5-methyl-1-hexen-3-one, and 1-(6-butyl-3,4-dihydro-2H-pyran-2-yl)pentanone. (1)as major components, as well as,2,3-dimethyl-1.,4-benzoquinone and 2-ethyl-3 methyl-1,4-benzoquinone as minor,constituents. The. dihydropyran 1-(6-butyl-3,4-dihydro-2H-pyran-2-yl)pentanone (1) is a new natural product, composed of two 1-hepten-3-one, subunits formally linked in a hetero-Diels-Alder reaction. The natural product was proven to be racemic, and its biogenetic origin is discussed.

Antimycobacterial activities of novel fluoroquinolones

Fifty-one novel 1-(cyclopropyl/2,4-difluorophenyl/t-butyl)-1,4-dihydro-6-fluoro-7-(sub secondary amino)-4-oxoquinoline-3-carboxylic acids were synthesized and evaluated for their antimycobacterial in vitro and in vivo against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC 2) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the synthesized compounds, 7-(3-(diethylcarbamoyl)piperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (7I) was found to be the most active compound in vitro with MIC of 0.09 mu M against MTB and MDR-TB respectively. In the in vivo animal model 7I decreased the mycobacterial load in lung and spleen tissues with 2.53- and 4.88-log10 protections respectively at a dose of 50 mg/kg body weight. (C) 2007 Elsevier Masson SAS. All rights reserved.

Iron(III) Catecholates for Cellular Imaging and Photocytotoxicity in Red Light

Iron(III) complexes Fe(L)(L') (NO3)]-in which L is phenyl-N, N-bis(pyridin-2-yl) methyl]methanamine (1), (anthracen-9-yl)N, N-bis(pyridin-2-yl) methyl] methanamine (2), (pyreny-1-yl)-N, N-bis(pyridin- 2-yl) methyl] methanamine (3-5), and L' is catecholate (1-3), 4-tert-butyl catecholate (4), and 4-(2-aminoethyl)benzene- 1,2-diolate (5)-were synthesized and their photocytotoxic proper-ties examined. The five electron-paramagnetic complexes displayed a FeIII/ Fe-II redox couple near similar to 0.4 V versus a saturated calomel electrode (SCE) in DMF/0.1m tetrabutylammonium perchlorate (TBAP). They showed unpre-cedented photocytotoxicity in red light (600-720 nm) to give IC50-15 mm in various cell lines by means of apoptosis to generate reactive oxygen species. They were ingested in the nucleus of HeLa and HaCaT cells in 4 h, thereby interacting favorably with calf thymus (ct)-DNA and photocleaving pUC19 DNA in red light of 785 nm to form hydroxyl radicals.

具有环氧化酶-2选择性抑制活性的多取代蒽醌的合成

1-甲基-2-甲氧羰基-3, 6, 8-三羟基-7-甲氧基蒽醌是从唐菖蒲干球茎中分离到的具有环氧化酶-2选择性抑制活性的多取代蒽醌类化合物。本文试图合成该化合物，实现了其类似物的合成，同时发现了几个未见报道的反应。 1．通过Diels-Alder 反应合成了关键中间体——3-甲基-5-羟基-1, 2, 4-苯三甲酸三甲酯，1-COOMe选择性水解产物与1, 2, 3-三甲氧基苯进行分子间Friedel-Crafts反应的产物再进行分子内Friedel-Crafts反应得到了目标产物的类似物1-甲基-2-甲氧羰基-3-羟基-6，7，8-三甲氧基蒽醌（路线1）。目标产物及其它类似物的合成正在进行中。 2．以乙酰乙酸甲酯和巴豆醛为原料，经过Michael加成、分子内的Aldol反应、芳香化、选择性甲酰化和还原反应，得到关键中间体2-甲基-3-羟甲基-6-甲氧基苯甲酸甲酯及其衍生物。通过该化合物与3，4，5-三甲氧基苯甲酸甲酯进行Friedel-Crafts烷基化反应得到了多取代的二苯基甲烷衍生物，拟进一步关环合成目标化合物（路线2）。 3．发现邻甲氧基苯甲酸甲酯中酯甲基可以被正丁基锂和仲丁基锂中烷基交换生成相应的酯，反应的机理不明确。当使用叔丁基锂时，得到的是邻甲氧基苯基叔丁酮，这个方法可以用来合成芳基叔丁酮类化合物。 4．以2-苄氧基-6-甲基苯甲酸甲酯为原料进行氯甲基化反应时，以苯和二氯乙烷作溶剂，发生了苄基的迁移和芳环的偶联，分别得到2，2'-二甲基-3，3'-二甲氧羰基-4，4'-二羟基联苯和2，2'-二甲基-3，3'-二甲氧羰基-4，4'-二羟基-5，5'-二苄基联苯。这是对称联苯合成的新方法。 5．水杨酸羟基邻对位的选择性甲酰化可以分别通过水杨酸和水杨酸甲酯用HMTA/CF3COOH来实现。 6．Lewis酸催化3，4，5-三甲氧基苄醇环化成1, 2, 3, 6, 7, 8, 11, 12, 13-nonamethoxyl-10,15-dihydro-5H-trbibenzo [a, d, g] cyclononene (NDTC)，产率(54%)高于已有方法（12%）。 Methyl 3,6,8-trihydroxy-7-methoxy-1-methylanthraquinone-2-carboxylate is a new COX-2 selective inhibitor isolated from Gladiolus gandavensis. Two strategies were investigated to synthesis this compound, in which some important reactions were discovered. 1. The key intermediate 5-hydroxy-3-methylbenzene-1,2,4-tricarboxylic acid 2,4-dimethyl ester was prepared via Diels-Alder reaction followed by selective hydrolysis of 1-COOMe. This compound was coupled with 1,2,3-trimethoxybenzene and the product undergo intramolecular Friedel-Crafts reaction to give methyl 3-hydroxy-5,6,7-trimethoxy-1-methylanthraquinone-2-carboxylate (1st route). The target compound and other analogues are being prepared with the same procedure. 2. The key intermediates methyl 3-hydroxymethyl-6-methoxy-2-methylbenzoate and its derivatives were prepared starting from crotonaldehyde and methyl acetoacetate via Michael addition, intramolecular aldol reaction, aromatization, formylation and reduction. The intermediates were coupled respectively with derivatives of gallic acid to give polysubstituted diphenylmethane. However, attempts to cyclize these compounds to the target compounds and analogues were not successful (2nd route). 3. In the process for ortho-lithiation of methyl 2-methoxybenzoate, the substrate converted respectively to n-butyl 2-methoxybenzoate and sec-butyl 2-methoxybenzoate when n-BuLi and sec-BuLi were used. However, tert-BuLi reacted with methyl 2-methoxybenzoate afford 2-methoxyphenyl tert-butyl ketone, which could be used to synthesize aryl tert-butyl ketones. 4. The transformtion of methyl 2-benzoxy-6-methylbenzoate to dimethyl 4,4'-dihydroxy-2,2'-dimethylbiphenyl-3,3'-dicarboxylate in benzene, and dimethyl 5,5'-dibenzyl-4,4'-dihydroxy-2,2'-dimethylbiphenyl-3,3'-dicarboxylate in 1,2-dichloroethane in the presence of ZnCl2 provides a new method for the synthesis of symmetric biphenyl. 5. The formylation of salicylic acid at C-5 and methyl 2-hydroxybenzoate at C-3 could be regioselectively realized by using HMTA/CF3COOH. 6. Racemic 1, 2, 3, 6, 7, 8, 11, 12, 13-nonamethoxyl-10, 15-dihydro-5H-trbibenzo [a, d, g] cyclononene was prepared via Lewis acids catalyzed trimerization of 3, 4, 5-trimethoxylbenzyl alcohol with yield (54%) higher than the reported procesure (12%).

Purification and characterization of recombinant truncated human interleukin-11 expressed as fusion protein in Escherichia coli

Mature human interleukin-11 (HuIL-11) is a cytokine consisting of 178 amino acid residues that results from scission of the N-terminal signal peptide, consisting of 21 amino acid residaues, from the corresponding nascent polypeptide. A DNA fragment encoding a truncated HuIL-11 (trHuIL-11), with an additional 5 amino acid residues removed from the N-terminus, was cloned into vector pGEX-2T between the BamHI site and the EcoRI site. Upon transformation with Escherichia coli BL21, the construct over-produced a glutathione S-transferase (GST)-fused protein in a soluble form after IPTG induction. The fusion protein was initially fractionated with butyl-Sepharose 4 fast flow column and by affinity chromatography using a GSH-Sepharose 4B column. On-site enzymatic release with thrombin gave the target protein at 96% purity as judged by SDS-PAGE and HPLC. Expression of the interleukin as a GST-fused protein thus greatly improved downstream processing. Subsequent biological activity assay suggested that trHuIL-11 had similar activity profile to the naturally produced sample and may be a promising candidate for further development as biopharmaceutical.

Colloidal microgel in removal of water from biodiesel

A series of poly(N-isopropylacrylamide) [pNIPAM]-based homo-polymer and co-polymer microgel particles were prepared by surfactant-free emulsion polymerisation. The co-monomers were acrylic acid. 4-vinylpyridine. butyl acrylate, 4-vinylbiphenyl and vinyl laurate. Co-monomers were added at a concentration of 10% (w/w) relative to the base monomer pNIPAM for the preparation of each co-polymer microgel. The co-monomers chosen vary by their organic chain length, polarity and pH sensitivity, as these should influence how the particles behave in aqueous and non-aqueous solvents. The effect of adding different types of co-monomer into the microgel structure was investigated with respect to their dispersibility in different solvents. These microgel particles have shown useful application in the removal of water from biodiesel prepared from rape seed. Karl Fischer experiments showed that microgel particles can be used to reduce the water content in biodiesel to an acceptable level for incorporation into internal combustion engines. (C) 2008 Elsevier B.V. All rights reserved.

Characterization of the physicochemical, antimicrobial, and drug release properties of thermoresponsive hydrogel copolymers designed for medical device applications

In this study, a series of hydrogels was synthesized by free radical polymerization, namely poly(2-(hydroxyethyl) methacrylate) (pHEMA), poly(4-(hydroxybutyl)methacrylate) (pHBMA), poly(6-(hydroxyhexyl)methacrylate) (pHHMA), and copolymers composed of N-isopropylacrylamide (NIPAA), methacrylic acid (MA), NIPAA, and the above monomers. The surface, mechanical, and swelling properties (at 20 and 37 degrees C, pH 6) of the polymers were determined using dynamic contact angle analysis, tensile analysis, and thermogravimetry, respectively. The T-g and lower critical solution temperatures (LCST) were determined using modulated DSC and oscillatory rheometry, respectively. Drug loading of the hydrogels with chlorhexidine diacetate was performed by immersion in a drug solution at 20 degrees C (

Poly(ethylene-co-acrylic acid) random copolymers : amphiphilic properties and self-assembly in aqueous medium

Les travaux de recherche présentés ici avaient pour objectif principal la synthèse de copolymères statistiques à base d’éthylène et d’acide acrylique (AA). Pour cela, la déprotection des groupements esters d’un copolymère statistique précurseur, le poly(éthylène-co-(tert-butyl)acrylate), a été effectuée par hydrolyse à l’aide d’iodure de triméthylsilyle. La synthèse de ce précurseur est réalisée par polymérisation catalytique en présence d’un système à base de Palladium (Pd). Le deuxième objectif a été d’étudier et de caractériser des polymères synthétisés à l’état solide et en suspension colloïdale. Plusieurs copolymères précurseurs comprenant différents pourcentages molaires en tert-butyl acrylate (4 à 12% molaires) ont été synthétisés avec succès, puis déprotégés par hydrolyse pour obtenir des poly(éthylène-coacide acrylique) (pE-co-AA) avec différentes compositions. Seuls les copolymères comprenant 10% molaire ou plus de AA sont solubles dans le Tétrahydrofurane (THF) et uniquement dans ce solvant. De telles solutions peuvent être dialysées dans l’eau, ce qui conduit à un échange lent entre cette dernière et le THF, et l’autoassemblage du copolymère dans l’eau peut ensuite être étudié. C’est ainsi qu’ont pu être observées des nanoparticules stables dans le temps dont le comportement est sensible au pH et à la température. Les polymères synthétisés ont été caractérisés par Résonance Magnétique Nucléaire (RMN) ainsi que par spectroscopie Infra-Rouge (IR), avant et après déprotection. Les pourcentages molaires d’AA ont été déterminés par combinaison des résultats de RMN et ii de titrages conductimètriques. A l’état solide, les échantillons ont été analysés par Calorimétrie différentielle à balayage (DSC) et par Diffraction des rayons X. Les solutions colloïdales des polymères pE-co-AA ont été caractérisées par Diffusion dynamique de la lumière et par la DSC-haute sensibilité. De la microscopie électronique à transmission (TEM) a permis de visualiser la forme et la taille des nanoparticules.

A square-planar nickel(II) monoradical complex with a bis(salicylidene)diamine ligand

The new square-planar Ni-II-N2O2 complex [Ni(L-Me)] (1(Me)), where L-Me, stands for the dianionic phenolato form of N,N'bis(3,5-di-tert-butyl-salicylidene)-4,5-dimethyl-1,2-phenyl- enediamine ((LH2)-L-Me), has been synthesised and fully characterised. X-ray crystallography was also used for the characterisation. The electrochemical one-electron oxidation of 1(Me) produces the thermally stable (within the temperature range 10-295 K) cationic species (1(Me))(+). The UV/Vis and X-band EPR experimental data, supported by DFT calculations, indicate that (1(Me))(+), is best described as a Ni-II monoradical complex and, thus, does NOT exist in a Ni-III ground state, in contrast to its demethylated counterpart [Ni(L-H)](+) (1(H))(+) below 170 K.

Mesomorphic behaviour in copoly(ester-imide)s of poly(butylene-2,6-naphthalate) (PBN)

Copolycondensation of N,N’-bis(4-hydroxybutyl)-biphenyl-3,4,3',4'-tetracarboxylic diimide at 20 and 25 mol% with bis(4-hydroxybutyl)-2,6-naphthalate produces PBN-based copoly(ester-imide)s that not only crystallise but also form a (smectic) mesophase upon cooling from the melt. Incorporation of 25 mol% imide in PBN causes the glass transition temperature (measured by DSC) to rise from 51 to 74 °C, a significant increase relative to PBN. Furthermore, increased storage- (G'), loss- (G'') and elastic (E) moduli are observed for both copoly(ester-imide)s when compared to PBN itself. Structural analysis of the 20 mol% copolymer by X-ray powder and fibre diffraction, interfaced to computational modelling, suggests a crystal structure related to that of α-PBN, in space group P-1, with cell dimensions a = 4.74, b = 6.38, c = 14.45 Å, α = 106.1, β = 122.1, γ = 97.3°, ρ = 1.37 g cm-3.