Disubstituted amino-, nitroso-, and nitrofluorenes: a physicochemical basis for structure-activity relationships in Salmonella typhimurium.

Abstract

Twenty-nine derivatives of fluorene were tested for mutagenic potency in four strains of Salmonella typhimurium with and/or without S9 microsomal activation. The effects of a second functional group on the mutagenic activity of an amino-, nitroso-, and nitrofluorene were correlated with its physical and chemical properties. When the functional group is conjugated by resonance, both inductive and resonance effects are determinants of mutagenic potency. Electron-withdrawing groups such as the halogens (F, C1, Br, and I), nitro, nitroso, and cyano at C-7 increased the mutagenic potency of 2-nitrofluorene. Electron-donating substituents such as hydroxy and amino groups at C-7 decreased the mutagenic potency of 2-amino, 2-nitroso-, and 2-nitrofluorene. Acetylation of a hydroxy or an amino group at C-7 increased the mutagenic potency of 2-nitrofluorene, presumably by decreasing the electron-donating properties of these groups. In contrast, acetylation of a nonresonance-conjugated amino group decreased mutagenic activity. The physical properties of a second functional group are expected to exert their effect(s) at three points in the metabolic activation of 2,7-disubstituted fluorene derivatives: initial reduction of the nitro group (redox effect), stabilization of the hydroxylamine (inductive effect), and stabilization/destabilization of the nitrenium ion (resonance and inductive effects). The relationships between the physical properties of a second functional group and their effects on biological activities of nitro- and aminofluorenes in the Ames Salmonella assay may be of predictive value in a first approximation of both the mutagenic and carcinogenic potency of chemicals with comparable structures such as fluoranthene and biphenyl.