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Perfluoro-4-isopropylpyridine was used as a building block for the two-step synthesis of a variety of macrocyclic systems bearing pyridine sub-units which were characterised by X-ray crystallography. Electrospray mass spectrometry revealed that complexation of either cations and, unusually, anions is possible depending on the structure of the macrocycle.
Derivatives of 4-aminophenylalkanoic acids where the amino groups is part of a 3-morpholinone or a 2-morpholine ring, substituted in position 2 with a methyl, phenyl, 2-thienyl or (2-cyclohexyl)phenoxymethyl residue are described. Pharmacological evaluation aimed at evidencing analgesic and anti-inflammatory activity gave no noteworthy results.
The synthesis of pyrrolo[1,2-a]quinoline derivatives from 1-arylpyrroles bearing an acetic acid or acetonitrile moiety on the benzene or pyrrole nucleus is described. Pyrrolo [1,2-a]quinoline derivatives have some pharmaceutical interest as cyclic analogues of 9H-pyrrolo[1,2-a]indole and 5H-pyrrolo[2,1-c] [1,4]-benzodiazepine, the basic structures of the antitumor antibiotics mitomycin C, anthramycin and tomaymycin.
Xanthones and acridones were synthesized from 3,4-difluoronitrobenzene and 2-fluorobenzaldehydes in two or three steps. The key step was nucleophilic aroylation catalyzed by imidazolidenyl carbene. The nucleophilic aroylation of 3,4-difluoronitrobenzene afforded 2,2'-difluoro-4-nitrobenzophenones. The cyclization of the difluorobenzophenones with O-nucleophile and N-nucleophile yielded 3-nitroxanthones and 3-nitroacridones, respectively. Indazole, quinolino[2,3-b]quinoxaline, and thianaphtho[2,3-b]quinoxaline derivatives were also synthesized via nucleophilic aroylation of 2,3-dichloroquinoxaline followed by cyclization with nucleophiles.
The anti-dithietane-1,3-dioxide --> syn-dithietane-1,3-dioxide isomerization reaction has been theoretically studied on the frame of MO theory both in the gas phase and in solution. In the gas phase the anti (II(a)) <--> syn (II(s)) equilibrium is slightly displaced to the anti isomer formation. The syn concentration ([Syn]) is ca. 36% in the gas phase, whereas in low polarity solvent, such as carbon tetrachloride, [Syn] is ca. 63%. In medium-high polarity solvents like acetonitrile and dimethyl-sulfoxide the [ anti]/[ syn ] ratio is ca. 0.37.
The ardeemins are a new family of secondary metabolites produced by submerged fermentation of a fungus which was isolated from a soil sample collected in Brazil. Based on taxonomic studies, the producing culture was identified as Aspergillus fischeri var. brasiliensis strain AB 1826M-35. 5-N-Acetylardeemin potentiated the cytotoxicity of the anticancer agent vinblastine in multidrug resistant human tumor cells.
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Several dioxouranium(VI) heterochelates with tetradentate monobasic hydrazone compounds (HL(n)) have been synthesized. The heterochelates of the type [(UO2)2(HL(n))(L(n))2(OAc)2(OH2)2]n have been characterized on the basis of elemental analyses, IR and electronic spectra, conductance and magnetic susceptibility measurements. The complexes are polymeric, non-electrolytes, diamagnetic and eight-coordinated. Wilson, G.F. matrix method, Badger's formula, Jones and El-Sonbati equations were used to determine the stretching and interaction force constants from which the U-O bond distances were calculated. The bond distances of these complexes were also investigated.
A new family of symmetrical bisquaternary compounds with semirigid linkers have shown to be highly specific for Choline Kinase (ChoK) inhibition and to exert antitumoural activity in cell lines and in mice. A three-parameter regression equation has been derived which satisfactorily describes the ex vivo inhibitory potency of ChoK of the title compounds. The electronic effect of the group at position 4 of the cationic head plays a critical role although the hydrophobic contribution, especially that of the linker, favors the ChoK inhibitory activity. The antiproliferative activity (in vitro assay) is correlated with the ChoK inhibition (ex vivo assay) through the electronic effect and a squared term of the overall lipophilicity of the molecules. We also provide in vivo evidence that ChoK is a novel target for the design of antitumoural drugs. All these results suggest that ChoK plays a crucial role in the onset of carcinogenesis.
A series of imidazo[1,2-b]pyridazine-2-carboxylic acids, esters and amides was synthesized and tested for antiinflammatory, analgesic and ulcerogenic activities. The ethyl esters were prepared by cyclocondensation of some 3-aminopyridazines with ethyl bromopyruvate, followed by hydrolysis or ammonolysis in order to obtain the corresponding acids and amides. The inhibitory activity on the carrageenan-induced edema in the rat paw and on writhes induced by acetic acid in mice was evaluated, as well as the ulcerogenic action on the rat gastric mucosa. The pharmacological activity was discussed in terms of structure-activity relationships. In particular, the analgestic activity shown by these carboxylic derivatives was compared with that found in other series of imidazo[1,2-b]pyridazine analogues previously examined.
The electrochemical properties of three nitroimidazoles, a nitropyrazole, a nitrofuran and three nitrobenzenoid compounds have been extensively investigated in a range of solvents. The reduction pathway for the nitro group is independent of the cyclic function to which it is attached, but is strongly influenced by the nature of the solvent. In aqueous media, generally, a single, irreversible 4-electron reduction occurs to give the hydroxylamine. In aprotic media (dimethylformamide, methylene chloride or dimethylsulphoxide), a reversible one-electron reduction takes place to form a stable nitro radical anion. At more negative values, a further 3-electron reduction occurs, irreversibly to give the hydroxylamine. In mixed aqueous-organic systems, intermediate behaviour is found, with the reversibility of the RNO2/RNO.-2 couple increasing with addition of organic medium. The control of the reduction pathway, by changing the electrolytic medium is discussed in relation to the biological activities of the drugs and identification of the short-lived reduction intermediate responsible for DNA damage.
The first direct generation of synthetically useful alpha-phosphonovinyl radicals was achieved by treatment of alpha-phosphonovinyl halides with a tributyltin radical. The alpha-phosphonovinyl radicals 2a-d were trapped with electron-rich olefins and an electron-deficient olefin to produce alpha-functionalized vinylphosphonates 3a-f in 16-55% yields. The alpha-phosphonovinyl radicals 7e-g containing the YCH2CH=CH2 (Y = O, CH2, S) substituent at the beta-position afforded mixtures of 5-exo and 6-endo cyclization products, 5e-g and 6e-g, in good yields. The 5-exo/6-endo product ratios increase in the following order of the beta-substituent: OCH2CH=CH2 > CH2CH2CH=CH2 > SCH2CH=CH2. The effects of the beta-substituents upon the cyclization reaction were discussed. Radical cyclization of alpha-phosphonovinyl radicals bearing functional groups such as geranyloxy, geranylthio, and (2-cyclohexen-1-yl)thio groups at the beta-position afforded 5-exo, 5-exo and 6-endo, and cis-fused-5,6-ring cyclization products incorporating an alpha,beta-unsaturated phosphonate unit within the ring, respectively, in good yields. The alpha-phosphonovinyl radical 20 underwent tandem radical cyclization-radical cyclization to produce a mixture of two isomeric bicyclo[4.3.0]nonenes including a vinylphosphonate moiety in high yield.
The standard free energy change (delta G0) for equilibrium dissolution in binary solvent mixtures is written as a sum of effects arising from solvent-solvent interactions (the general medium effect), solvent-solute interactions (the solvation effect), and solute-solute interactions (the intersolute effect). The general medium effect is given by gA gamma, where g is a curvature correction factor to the surface tension (gamma) and A is the molecular cavity surface area. A new feature is the definition of gamma to be that value appropriate to the equilibrium mean solvation shell composition. The solvation effect is modeled by stoichiometric stepwise competitive equilibria between the two solvent components for the solute. The intersolute effect includes the crystal energy and solution phase interactions. In this work, water was solvent component 1, and various miscible organic cosolvents served as solvent component 2. Relating all data to the fully aqueous solution gives an explicit expression for delta M delta G0, the solvent effect on the free energy change, as a function of the mole fractions x1 and x2. This function is a binding isotherm. Nonlinear regression leads (for a two-step solvation scheme) to estimates of the solvation exchange constants K1 and K2 and the parameter gA. This relationship was applied to 44 systems comprising combinations of 31 solutes and eight organic cosolvents. Curve fits were good to excellent, and most of the parameter estimates had physically reasonable magnitudes.
Due to the close homology between bacterial and tumor cell transporter proteins, some antiplasmid and anticancer compounds were tested for their ability to reserve the multidrug resistance (mdr) of lymphoma cells. Some known anticancer medicines such as platidiam, novantron, fluorouracil, bleomycin and methotrexate were ineffective/while vinca alkaloids exerted a strong reversal effect on the mdr of lymphoma cells. The structurally related reserpine and yohimbine do not affect the activity of efflux pump. Some selected antitumor phenothiazines and benzo[a]phenothiazines, including trifluoperazine inhibit the P-glycoprotein (pgp) function. This fact is independent from the antiproliferative- or differentiation inducing effects. Since the polylactosamine specific tomato lectin prevents the action of the chemosensitizers tested, it is supposed that the site of action of phenothiazines can be at the 1st loop in the transmembrane glycoprotein. The efflux pump activity of the pgp in brain capillary endothel which is responsible for blood brain barrier (BBB) was also inhibited by some phenothiazines. However, the tomato lectin sensitivity of pgp was different in mouse lymphoma and human brain capillary endothelial cells. The mdr-gene expression of the mouse lymphoma cells (which were transfected with the human mdr-1 gene) could be reduced by phenothiazines such as promethazine and trifluoperazine, when the cells were cultured in the presence of 0.5 microgram/mL phenothiazines. Further synergism was found between two resistance modifiers i.e. verapamil and trifluoperazine on the inhibition of mdr-glycoprotein.
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