Novel 5,8-Diazabenzo[c]phenanthrenes: Synthesis and Mutagenicity

Abstract

Abstract The polycyclic aromatic hydrocarbons have been recognized as carcinogens and mutagens since the early part of this century. More recently their aza and polyaza derivatives have been shown to have the same biological activity. A major source of these compounds is the combustion of fresh or metamorphosed plant materials; this contributes to the environmental burden of, and exposure to, these carcinogens. We report the synthesis and characterization of a series of novel 5,8-diazabenzo[c]phenanthrenes which are isosteric with the known epidermal carcinogen benzo[c]phenanthrene but have not yet been reported as components of soot or diesel particulate matter. The synthesis of the compounds exploits a versatile, double Friedlander reaction between the appropriately substituted 2,2′-diaminobenzophenone and β-diketones, with yields of purified product ranging from 30–90%. The nucleophilic substitution of these diazabenzophenanthrenes with ethanolamine is also described. This strategy will enable further elaboration of these heterocyclic nuclei at a later date. Mutagenicity testing of these agents was performed using spot tests and in Ames plate-incorporation assays using Escherichia coli WP2 and WP2uvrA as test organisms. The plate-incorporation assays were performed in the presence or absence of metabolic enzymes contained in the S9 liver fraction from Aroclor 1254-induced rats, to investigate whether bioactivation of the diazabenzophenanthrenes contributed to their toxicity. No differences between these two protocols were observed, with neither test showing reversion to prototrophic behaviour. Furthermore, the compounds were not toxic to the test organism. These initial results suggest that these compounds are not mutagenic in the Ames tests employed.