Roland E. Lehr

Metabolic activations of polycyclic hydrocarbons

Considerable evidence now points to 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrenes as ultimate mutagenic and carcinogenic forms of benzo(a)-pyrene. Quantum mechanical calculations have been performed to assess the possible general role of diol epoxides in polycyclic aromatic hydrocarbon (PAH) mutagenesis and carcinogenesis. The calculations enable a prediction of relative reactivity (ease of carbonium ion formation) for diol epoxides derived from a single PAH and also for diol epoxides from different PAHs. The calculated reactivity has so far been found to provide a good estimate of diol epoxide mutagenicity. Results of the metabolic activation of benzo(a)anthracene dihydrodiol derivatives and of the mutagenicity of benzo(a)anthracene diol epoxides are reported. Limitations inherent in predictions of polycyclic aromatic hydrocarbon carcinogenicity using a model based upon the calculated reactivity of a potential metabolite are discussed.ZusammenfassungZahlreiche Beweise sprechen heute für 7,8-Dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene als ultimale mutagene und carcinogene Formen des Benzo(a)pyrens. Quantenmechanische Berechnungen wurden durchgeführt, um die mögliche allgemeine Rolle von Diolepoxiden bei der Mutagenese und Carcinogenese von polyzyklischen aromatischen Kohlenwasserstoffen (PAH) abzuschätzen. Die Berechnungen ermöglichen eine Vorhersage der relativen Reaktivität (Leichtigkeit der Carboniumionenbildung) sowohl für Diolepoxide, die von einem einzelnen PAH abgeleitet sind, als auch für Diolepoxide von verschiedenen PAHs. Es wurde gefunden, daß die berechnete Reaktivität eine gute Abschätzung der Mutagenität von Diolepoxiden liefert. Ergebnisse über die metabolische Aktivierung von Benzo(a)anthracendihydrodiolderivaten und über die Mutagenität von Benzo(a)anthracendiolepoxiden werden berichtet. Vorhersagen der PAH-Carcinogenität mit Hilfe eines Modells, das auf der berechneten Reaktivität eines potentiellen Metaboliten basiert, unterliegen Beschränkungen, die diskutiert werden.

Aza-polycyclic aromatic hydrocarbon carcinogenicity: predictions of reactivity of tetrahydrobenzo ring epoxide derivatives

Abstract Huckel and perturbational molecular orbital calculations suggest that the position of nitrogen substitution has an important influence on reactivity of tetrahydroepoxides of aza-polycyclic aromatic hydrocarbons.

Synthesis of polycyclic aromatic hydrocarbon 2′-deoxyadenosine analogs

Abstract The chemical synthesis of polycyclic aromatic hydrocarbon (PAH) modified 2′-deoxyadenosine analogs has been achieved. Two model adducts, incorporating a naphthalene (Np) and a benzo[a]pyrene (BaP) unit have been prepared.

Acetoxylation at benzylic positions of tetrahydrobenzo rings with DDQ in acetic acid

Abstract Good-excellent yields of ironoacetoxy derivatives at benzylic positions are obtained upon reaction of polycyclic aromatic hydrocarbons (PAH) containing an angular tetrahydrobenzo ring with DDQ in acetic acid.

Structure-reactivity indices for the hydrolysis of diol epoxides of polycyclic aromatic hydrocarbons

Abstract Several different computational parameters have been used in an attempt to predict relative reactivity of carcinogenic bay-region diol epoxides. The correlation of experimentally observed hydrolytic reactivity with these parameters is described.

Tetrahydroepoxides and diol epoxides of benz[c]acridine

Abstract The chemical synthesis and NMR characterization of the benzo ring tetrahydro- and diol epoxides of the carcinogen benz[c]acridine are described.

Dihydrodiols and diol epoxides of dibenzo[a,i]-and [a,h]pyrene

Abstract Syntheses of dihydrodiols and highly mutagenic diol epoxides of the carcinogenic polycyclic aromatic hydrocarbons dibenzo[a,i]-and [a,h]pyrene are described.

Synthesis and Neurotoxic Potential of Racemic and Chiral Dihydroxytetrahydroquinoline Derivatives

Abstract The synthesis and preliminary neurotoxic investigation of (±), (+) and (−)-3-amino-6,7-dihydroxy-1,2,3,4-tetrahydroquinoline, (±)-3-amino-6,8-dihydroxy-1,2,3,4-tetrahydroquinoline and (±)-3-aminomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroquinoline are described. While exhibiting relatively no dopamine and only moderate norepinephrine depletions, these compounds elicit serotonin depletions equal to those provided by the well-known serotonergic neurotoxin 5,7-dihydroxytryptamine in whole mouse brain.

BAY-REGION ACTIVATION OF POLYCYCLIC AROMATIC HYDROCARBONS TO ULTIMATE MUTAGENS AND CARCINOGENS

Publisher Summary Gross chemical reactivity of diol epoxides—a fundamental assumption of the bay-region theory—helps in the understanding of hydrocarbon-induced carcinogenicity. However, several other structural and metabolic factors must be taken into account for specific hydrocarbons. Thus, regiospecificity of the cytochrome P-450 system must be such that a significant amount of the active dihydrodiol can be formed with the aid of epoxide hydrase. The conformation and enantiomeric makeup of this dihydrodiol are also important. The extent of formation and diastereomer as well as enantiomer composition of the diol epoxides formed from the dihydrodiol by the cytochrome P-450 system are dependent upon these factors. Conformation of diol epoxides also determines biological activity. This chapter discusses several metabolic factors that play determining roles in establishing relative carcinogenicity for the polycyclic hydrocarbons; however, other factors such as rates of repair of chemical damage to the cell and differences in immunocompetence may prove to be important.

Improved High-Yield Synthesis of Polycyclic Aromatic Hydrocarbon Amino Tribenzoates, Nucleophilic Components for Synthesis of Diol Epoxide-Nucleoside Adducts

Abstract This report describes an improved high-yield synthesis of amino tribenzoates derived through a trans-ring opening of diol epoxides. A significant difference in the relative reactivities of benzo[a]pyrene series-1 and series-2 diol epoxide diastereomers with LiN3 has been noted. Facile triacylation of the azido triols derived through this ring-opening with benzoyl cyanide and reduction using PtO2 afforded the corresponding amines in high yields.