The electronic structure of 2-acetamidofluorene and its related compounds is calculated using the frontier electron method, which has been established by the present authors, and compared with the chemical reactivity, formation of many phenolic metabolites, and carcinogenicity of these compounds.
The experimental positions of attack in fluorene, aminofluorene, and 2-acetamidofluorene are explained well by the frontier electron density, whereas the total π-electron deisity and localization energy fail to explain the experimental resuits of fluorene.
The formation of phenolic metabolites after ingestion of 2-acetamidofluorene is discussed by the frontier electron density of the molecule and it is found that the relative amounts of many ring-hydroxylated products are parallel to the order of the frontier electron density for radical attack. In view of this finding, the mechanism of ring hydroxylation of 2-acetamidofluorene is deemed to be radical in nature, and a similarity in reaction nature to other carcinogens such as aromatic hydrocarbons and azo compounds is pointed out.
The carcinogenicity of 2-acetamidofluorene and its related compounds is compared with theoretical index and an intimate correlation is found between the hepatocarcinogenicity of these compounds and the frontier electron distribution (approximate superdelocalizability) for nucleophilic attack at the 4-position. From this fact, it is supposed that the binding of the 4-position of these compounds with the nucleophilic (electron-rich) center in the body might be intimately connected with the formation of a tumor. This is an additional support of the previous supposition.
The nature of the binding receptor is discusssed in connection with the similarity between the theoretical conclusion and the property of binding proteins disclosed by experiments.
The sterical resemblance between the various kinds of chemical carcinogens is mentioned in regard to the hepatocarcinogenicity and the skin cancer-producing activity of aromatic hydrocarbons, azo compounds, 4-nitroquinoline 1-oxide, and 2-2-acetamidofluorene. Also attention is directed to the possible importance of the nitrogen atom in hepatocarcinogenic compounds.
Re-examination of the role of the K-region carbons in aromatic hydrocarbons is made in view of the sterical resemblance between the aromatic hydrocarbons and 4-nitroquinoline 1-oxide derivatives.
