John Pataki

Adrenal destruction and cancer induced by hydroxyalkyl derivatives of 7, 12-dimethylbenz(a)anthracene

Abstract Six new derivatives of benz(a)anthracene were found to cause massive and selective destruction of adrenal cortex of young adult female rats. The molecular requirements of the adrenocorticolytic agents are: (i) they have two and only two substituents; (ii) a methyl group at position 12 was mandatory; (iii) substituents at position 7 possessed an oxygen function or chloromethyl group. The hydroxyalkyl group diminishes or eliminates carcinogenicity of the parent compound.

Polycyclic aryloxiranes: A new class of carcinogens

Summary Metabolism of carcinogenic hydrocarbons is known to afford K-region and non-K-region oxides, both of which exhibit significant biological activity. Synthesis of a new class of oxide derivatives of polycyclic hydrocarbons, the aryloxiranes, is now described. A series of aryloxiranes and a related series of vinyl analogs were synthesized from the corresponding aldehydes via the Corey and Wittig reactions, respectively. Preliminary tests indicate the oxirane, formyl, and vinyl derivatives of benzo(a)pyrene and benz(a)anthracene to be moderately active carcinogens, while the related derivatives of the naphthalene and anthracene ring systems are inactive.

Mutational specificity of the syn 1,2-dihydrodiol 3,4-epoxide of 5-methylchrysene

The mutational specificity of the syn dihydrodiol epoxide of 5-methylchrysene in the supF gene of the pSP189 vector was examined. Transversion mutations at GC pairs predominated with G --> T and G --> C changes accounting for 42 and 21% of total base change mutations. The types of mutations found reflect the previously determined chemical preference of this reactive species for reaction with deoxyguanosine residues in DNA.

Conformations of complexes derived from the interactions of two stereoisomeric bay-region 5-methylchrysene diol epoxides with DNA.

The reaction mechanisms of two isomeric bay-region diol epoxides of 5-methylchrysene (trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (DE-I) and trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-methylchrysene (DE-II) with double-stranded DNA in aqueous solutions were studied utilizing kinetic flow dichroism and fluorescence techniques. As in the case of the previously studied benzo(a)pyrene-7,8-diol-9,10-oxide isomers (BaPDE), both DE-I and DE-II rapidly form intercalation-type complexes (association constants K = 2700 and 1500 M-1 respectively in a neutral 5mM phosphate solution). The physically bound diol epoxide molecules react on time scales of minutes to form predominantly tetraols; a greater fraction (6 +/- 1%) of DE-I than of DE-II (2-3%) molecules react with the DNA to form covalent products. The DE-II isomer is characterized by a greater reactivity than DE-I, and the rates of reaction are markedly accelerated in the presence of DNA in both cases. The linear dichroism spectra of the covalent adducts reveal that the conformations of both types of adducts are similar, with the long axes of the phenanthrenyl chromophores tilted, on the average, at angles of 38-52 degrees with respect to the average orientations of the transition moments (at 260 nm) of the DNA bases. The conformations of the covalently bound DE-I and DE-II molecules resemble those observed in the case of the highly tumorigenic (+) enantiomer of anti-BaPDE.(ABSTRACT TRUNCATED AT 250 WORDS)

Dibenz[a,c]anthracene: Electrophilic substitution and synthesis of phenol isomers

Abstract Efficient syntheses of the 3-, 9-, 10-, and 11-phenol isomers of dibenz[a,c]anthracene (DBa,cA) and 2,3-dihydroxy-DBa,cA are described. Bromination of DBa,cA with bromine in CH2Cl2 gave 10-bromo-DBa,cA and not 9-bromo-DBa,cA predicted theoretically. On the other hand, bromination of DBa,cA with NBS and FeCl3 furnished 9-bromo-DBa,cA.

Synthesis and conformation of 2-fluoro-3-ketoestrane derivatives

Abstract Treatment of 3-methoxy-17β-acetoxyestra-2,5(10)-diene with perchloryl fluoride in aqueous dioxane or tetrahydrofuran yielded a 2-fluoro-3-ketosteroid with unusual properties. Unlike the known 2α-fluoro-19-nortestosterone, this fluoroketone possessing a 5(10) double bond easily lost hydrogen fluoride to form estradiol 17-acetate; aromatization took place on melting, on exposure to pyridine or acid or even during chromatography on silica gel or Florisil. Because of the Δ-5(10) structure and the absence of the C 19 Me group, it is difficult to infer the exact orientation of the 2-fluorine substituent from its effect on the NMR spectrum, CD or the CO absorption in the IR. However, the properties of certain derivatives suggested that the fluorine substituent was 2β. Treatment of the unsaturated fluorketone with peracid gave a mixture of epoxides which on basic hydrolysis furnished two 2-fluoro-10-hydroxy-17-acetoxyestr-4-en-3-ones epimeric at C 10 . The UV and NMR spectra of the 10α-hydroxy epimer indicated an equatorial 2β-orientation of fluorine, whereas the 10β-hydroxy epimer showed an axial 2β-fluorine substituent which could be isomerized by acid to the more stable equatorial 2α-configuration.

Analysis of syn- and anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene- deoxyribonucleoside adducts by boronate chromatography

The Servacel DHB (m-dihydroxyborylphenylaminoethyl cellulose) chromatographic procedure developed by Sawiki et al. (Cancer Res., 43,3212-3218, 1983) for analysis of 7,12-dimethylbenz[a]anthracene (DMBA)-DNA adducts was applied to analyze syn- and anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (DE-I)-deoxyribonucleoside adducts. Identical elution conditions to whose developed for the DMBA adducts were employed. While the results were similar to those obtained in the DMBA system, some of the anti-DE-I-deoxyribonucleoside adducts eluted with the buffer system used for elution of syn-adducts. Complete resolution of the anti- and syn-adducts was obtained when modified elution conditions as developed by Pruess-Schwartz et al. (Cancer Res., 44, 4104-4110, 1984) for analysis of syn- and anti-7 alpha-8 beta-dihydroxy-9 beta, 10 beta-epoxy-7,8,9,10-tetrahydrobenzo[a]-pyrene--DNA adducts were applied. Based on this chromatographic procedure about 15% of the DE-I-deoxyribonucleoside adducts, formed in mouse skin DNA upon treatment with 5-[3H]methylchrysene (MeC), originated from syn-DE-I.

Synthesis of the Diol Epoxide Metabolites of Carcinogenic PAH

Abstract The active metabolites of alternant carcinogenic polycyclic aromatic hydrocarbons (PAH) with 4-5 fused rings are now readily available through synthesis. Development of new synthetic methodologies that are more efficient and are also applicable to larger PAH and to nonalternant PAH will be discussed. Syntheses of the unusual diol epoxide metabolites of the methylene-bridged PAH 4H-cyclopenta[def]chrysene, in both unsubstituted and substituted bay regions will be described. The latter is the first example of diol epoxide in which the epoxide function is located in an alkyl-substituted bay region site. Syntheses will also be outlined of the large polyarene benzo[s]picene, and its fjord region dihydrodiol and diol epoxide metabolites via a novel route.