Peter P. Fu

Molecular orbital theoretical prediction of the isomeric products formed from reactions of arene oxides and related metabolites of polycyclic aromatic hydrocarbons

Abstract MO theoretical calculations based on the perturbational method of Dewar provide good correlation between predicted and observed structures of products formed during: (1) isomerization of arene oxides to phenols; (2) hydration and nucleophilic addition to arene oxides; and (3) dehydration of arene dihydrodiols. The method is equally applicable to the arene oxides, dihydrodiols, etc. derived from carcinogenic and noncarcinogenic polycyclic hydrocarbons. Extension to the related enzymatic reactions occurring during metabolism of carcinogenic hydrocarbons and to the reactions of the biologically active arene diolepoxides and aryloxirenes suggests the potential utility of this approach in predicting (a) metabolite structure and (b) the structural requirements for carcinogenic and mutagenic activity.

Evidence for a 2,3-epoxide as an intermediate in the microsomal metabolism of benzo[a]pyrene to 3-hydroxybenzo[a] pyrene

Summary A synthetic benzo[a]pyrene (BP) specifically labeled with deuterium at the 3-position was incubated with rat liver microsomes in the presence of NADPH and oxygen. Mass spectral analysis of the metabolites isolated by high pressure liquid chromatography indicated that the 3-hydroxybenzo[a]pyrene (3-OH-BP) and BP-3,6-quinone retained 29% and 15% of the deuterium label respectively, whereas the BP 4,5-, 7,8-, and 9,10- diols, 9-OH-BP, BP-1,6-quinone, and BP-6,12-quinone retained essentially all the deuterium label. The results indicate that at least 29% of the 3-OH-BP detected as metabolite is formed through a 2,3-epoxide intermediate which rearranges spontaneously via an NIH shift mechanism to 3-OH-BP. At least 15% of the BP-3,6-quinone detected as a metabolite is derived from the enzymatically formed 3-OH-BP.

Regiospecific catalytic hydrogenation of polynuclear hydrocarbons

Durch katalytische Hydrierung von Benz(a)anthracen (II) mit Wasserstoff an Pd/Cunter milden Bedingungen entsteht in 97%iger Ausbeute regiospezifisch das 5,6-Dihydroderivat (I), wahrend die Hydrierung mit Wasserstoff an Pt in 95%iger Ausbeute zum 8,9,10,l 1- Tetrahydroderivat (III) sowie in 5%iger Ausbeute zum 7,12-Dihydroderivat (IV) fuhrt.

Application of CNDO2 theoretical calculations to interpretation of the chemical reactivity and biological activity of the syn and anti diolepoxides of benzo[a]pyrene

Abstract CNDO 2 molecular orbital theoretical calculations performed on the anti and syn diolepoxides ( 1 and 2 ) of the potent carcinogen benzo[ a ]pyrene provide insight into the molecular structure and reactivity of these mutagenic and carcinogenic hydrocarbon metabolites. Hydrogen-bonded interaction between the 7-HO proton and the epoxide oxygen atom of 2 is shown to be absent in the normal semichair conformation of the tetrahydro ring, (H…O bond distance = 2.7 A), but is energetically favored in a somewhat distorted puckered structure (H…O bond distance = 1.7 A). Unexpectedly, internal H-bonding alters the relative electron density at C 9 and C 10 , leading to prediction of the former as the more electrophilic center. Since all reactions of 2 take place exclusively at C 10 , transannular H-bonding is concluded not to contribute significantly to the structure of 2 . Diolepoxide reactions with both weak and strong nucleophiles and with DNA are discussed and the mechanisms interpreted in terms of molecular structure as determined by the theoretical calculations.

Comparative reactivities of diolepoxide metabolites of carcinogenic hydrocarbons with ØX174 viral DNA

Abstract The OX174 DNA assay system developed earlier is utilized to determine the comparative reactivities with nucleic acid of the diolepoxide metabolites of a series of polycyclic aromatic hydrocarbons varying in carcinogenic potency. The infectious OX174 viral DNA is exposed to the hydrocarbon derivative for 10 min., then infectivity of the treated DNA is assayed by incubation with E. coli spheroplasts, counting plaque formation on agar plates. The bay region diolepoxides of benzo[a]-pyrene, chrysene, and dibenz[a,h]anthracene, implicated as the ultimately active carcinogenic metabolites of the parent hydrocarbons, exhibit potent viral inhibitory activity. On the other hand no correlation is evident between viral inhibitory activity and either the location of the diolepoxide function in a bay region or the theoretically calculated β-delocalization energies (ΔEdeloc.) of the carbonium ion arising from opening the epoxide ring. The significance of these findings with respect to theories of carcinogenesis is discussed.

Benzo[a]pyrene-7,8-dihydrodiol: Selective binding to single stranded DNA and inactivation of ØX174 DNA infectivity

Abstract When single-stranded OX174 DNA is exposed to certain dihydrodiol derivatives of benzo[a]pyrene and benz[a]anthracene, inhibition of viral DNA infectivity is observed. Binding studies with labeled trans -7,8-dihydrodiol of benzo[a]pyrene and anti -benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide indicate that the diol preferentially reacts with single-stranded DNA, whereas the diolepoxide reacts equally well with both single- and double-stranded DNA, as well as with RNA. Also, the diol and diolepoxide derivatives show a marked difference in their capacity to complex with specific deoxyhomopolymers, i.e., Poly dI. These observations suggest that the diol and diolepoxide derivatives recognize different binding sites in nucleic acids, and that the diol derivative may play an important role in mutagenesis and carcinogenesis induced by polycyclic aromatic hydrocarbons.