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The relationship between mutagenic activity and chemical structure was studied for 54 polycyclic compounds using two approaches: multiple linear regression analysis and artificial neural networks. Structural fragments, quantum chemical indices, and hydrophobicity (octanol-water partition coefficient) were used as descriptors (properties of the molecules introduced in the model). Both linear regression equations and nonlinear relationships obtained with the help of a neural network were shown to accurately predict mutagenic activity for the compounds structurally similar to those in the training sample. The introduction of experimentally selected descriptors is substantiated to verify the proposed mechanism of related compounds mutagenic activity.
The mechanism of the cycloaddition reaction of forming a germanic hetero-polycyclic compound between singlet alkylidenegermylene and ethylene has been investigated with MP2/6-31G* method, including geometry optimization and vibrational analysis for the involved stationary points on the potential energy surface. The energies of the different conformations are calculated by CCSD(T)//MP2/6-31G* method. From the surface energy profile, it can be predicted that the dominant reaction pathway for this reaction consists of three steps: the two reactants first form a three-membered ring intermediate INT1 through a barrier-free exothermic reaction of 35.4 kJ/mol; this intermediate then isomerizes to an active four-membered ring product P2.1 via a transition-state TS2.1 with a barrier of 57.6 kJ/mol; finally, P2.1 further reacts with ethylene to form the germanic hetero-polycyclic compound P3, for which the barrier is only 0.8 kJ/mol. The rate of this reaction path considerably differs from other competitive reaction paths, indicating that the cycloaddition reaction has an excellent selectivity.
A method useful as a preconcentration technique for isolating mutagens and carcinogens is described. Cotton bearing covalently linked copper phthalocyanine trisulphonate as ligand (blue cotton) can adsorb selectively compounds having three or more fused rings. The adsorption takes place in aqueous media, involving 1:1 complex formation between the ligand and the polycyclic compound. The desorption can be done by elution with organic solvents, most effectively with methanol containing ammonia. As many important environmental mutagens and carcinogens are polycyclics, this adsorption is useful as a means of extracting this class of materials from crude samples such as food, urine and river waters. The use of copper phthalocyanine as a ligand for chromatographic supports has recently been initiated, yielding promising results for the effective separation of polycyclic aromatic compounds from each other.
Polycyclic compounds having linearly-fused six-membered rings can be readily prepared by various modes of cyclization from dienediynes, which were synthesized through the nickel-catalysed alkynylstannylation of 1,2-dienes followed by the palladium-catalysed oxidative homocoupling of the resulting alkenylstannanes.
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[reaction: see text] A highly useful method for the construction of polycyclic compounds based on the amine-controlled exo- and endo-selective cyclizations of omega-alkynyl silyl enol ethers catalyzed by W(CO)5L is reported. When bis-alkynyl silyl enol ethers were treated with a catalytic amount of W(CO)6, DABCO, and water under photoirradiation, synthetically useful tricyclic ketones were obtained in good yield.
A simple method for the preparation of fused polycyclic compounds by an intramolecular cyclization of propargylic alcohols bearing an alkene moiety at a suitable position has been developed, where the presence of both Ru and Pt catalysts promotes a sequence of catalytic cycles in the same medium. This sequential system can be applied to an intermolecular reaction between a propargylic alcohol and an alkene to obtain the corresponding bicyclo[3,1,0]hex-2-ene derivative. These sequential reactions provide a conceptually new type of cycloaddition system between propargylic alcohols and alkenes.
There is a significant correlation between the occurrence of pancreatic islet amyloid and beta-cell failure in advanced type II diabetes mellitus. Islet amyloid is composed primarily of the fibrillar form of the pancreatic hormone, amylin. Using thioflavin-T fluorescence binding and radioprecipitation assays, we investigated whether or not a series of small tricyclic compounds, tetracycline or Congo Red could interfere with the conversion of synthetic human amylin into its insoluble amyloid form. Of the compounds investigated, incubation of human amylin with a 20-fold molar excess of either Congo Red or Acridine Orange resulted in significant inhibition in the rate of amyloid formation. With Congo Red, maximal inhibition effectively occurred at a 1:1 molar ratio or greater over human amylin, whereas inhibition by Acridine Orange was dose-dependent. A 20-fold molar excess of the compound tetracycline also decreased insoluble amyloid content after extended incubation periods of approx. 20 h. Amyloid fibril morphology in the presence of tetracycline, as measured by transmission electron microscopy, was characterized by short fragmented fibrils compared with the longer and denser appearance of fibrils formed by amylin alone. These findings show that polycyclic compounds can suppress the formation of amyloid by human amylin, providing support for an alternative approach to peptide-based strategies by which islet amyloid formation could be modulated.
The polarographic reduction of a series carcinogenic and noncarcinogenic polycyclic nitrogen compounds in anhydrous dimethylsulfoxide containing tetrabuthylammonium perchlorate as supporting electrolyte has been studied. The obtained results were compared with the number or with the position of nitrogen atoms in the molecules and with their carcinogenic activity. The values of half-waves potentials generally confirmed the mechanism proposed for the reduction of aromatic polycyclic carcinogenic hydrocarbons based on the polarographic experiments in dimethylsulfoxide. Agreement of the obtained results with the data reported by polarographic study in anhydrous dimethylformamide indicates, that the polarographic behavior of polycyclic nitrogen compounds in dimethylsulfoxide is very similar.
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Reduction of half-wave potentials and the mechanism of reduction of 20 polycyclic nitrogen compounds were studied on a dropping-mercury electrode in anhydrous dimethylformamide using tetrabuthylammonium perchlorate as the supporting electrolyte. The measured values of the reducing half-wave potentials of the polycyclic aza-compounds were compared in view of their carcinogenic activity with parental carcinogenic polycyclic hydrocarbons. Electrochemical measurements have confirmed that the size of the shift in reducing potentials towards the more positive values and the decline of the carcinogenic activity generally depend on the number and position of the nitrogen atoms in the molecule of the polycyclic nitrogen compound under study. At the same time, the experimental electrochemical measurements were matched with the results of the quantum-chemical calculations of the molecular orbitals and this showed a good agreement to exist between the values of reducing half-wave potentials obtained by experimental measurement and by calculation.
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We report the synthesis and arraying of 29 400 structurally diverse and complex polycyclic carbocycles using diversity-oriented synthesis (DOS) and the "one bead-one stock solution" technology platform. Skeletal diversity, a difficult challenge in DOS, was achieved with a branching reaction pathway using one or two Diels-Alder reactions. This pathway yields small molecules having 10 different skeletons.
1. 9,10-Epoxy-9,10-dihydrophenanthrene is converted by rats into trans-9,10-dihydro-9,10-dihydroxyphenanthrene and its conjugates and into N-acetyl-S-(9,10-dihydro-9-hydroxy-10-phenanthryl)-l- cysteine. Small amounts of 9-phenanthryl sulphate and glucosiduronate are also formed, together with 9-hydroxy-10-phenanthryl sulphate. 2. The epoxide readily rearranges to 9-hydroxyphenanthrene and reacts with water to give the dihydrodihydroxy compound and with N-acetylcysteine to give the mercapturic acid. One of the diastereoisomeric forms of the methyl ester of the mercapturic acid is identical with the ester of the mercapturic acid excreted by rats dosed with the epoxide or by rats and rabbits dosed with phenanthrene. 3. A rat-liver homogenate converts the epoxide into trans-9,10-dihydrodihydroxyphenanthrene and S-(9,10-dihydro-9-hydroxy-10-phenanthryl)glutathione. The latter compound was not formed when boiled rat-liver homogenate was used, but was formed chemically from the epoxide and glutathione under more vigorous conditions. 4. The results provide further indications that the metabolism of aromatic hydrocarbons involves the intermediary formation of epoxides.
In both 9,10-dimethoxy-11-oxatricyclo[6.2.1.0(2,7)]undeca-4,9-diene-3,6-diol, C(12)H(16)O(5), (I), and 5,6-dimethoxy-3,7-dioxatetracyclo[6.4.0.0(2,6).0(4,12)]dodec-9-en-11-ol, C(12)H(16)O(5), (II), the hetero-oxygen-containing five-membered rings have an envelope conformation. The six-membered rings are in a boat conformation in compound (I), and in (II), one is in a half-boat and the other is in a slightly distorted boat conformation. The molecules in both compounds interact through classical hydrogen bonds and C-H.O contacts.
The electrooxidation of polycyclic carcinogenic hydrocarbons in dimethylformamide solutions was studied by polarography. The results generally have confirmed that a correlation exists between oxidation potentials and carcinogenic activity of the studied polycyclic aromatic hydrocarbons. The half-wave potentials of the polarographic curves have been found to be directly related to the root xn of the Hückel secular equation for the highest bonding orbital and to the reduction potentials measured in dimethylformamide.
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