Comparative adduct formation of 4-aminobiphenyl and 2-aminofluorene derivatives with macromolecules of isolated liver parenchymal cells.

Isolated parenchymal cells of rat liver have been used in a study of the metabolic activation of derivatives of the carcinogens 4-aminobiphenyl and 2-aminofluorene. The formation of adducts of these compounds with cellular RNA and protein has been taken as evidence of their transformation to metabolites that are capable of spontaneous reaction with tissue macromolecules. The hydroxamic acid N-hydroxy-N-4-acetylaminobiphenyl was bound to RNA to a greater extent than were the amino-, hydroxylamino-, nitroso-, nitro-, acetylamino-, or azoxybiphenyl derivatives. RNA adducts of the hydroxamic acid retained little of the acetyl group. The structural requirements for binding and the nature of the bound derivatives are consistent with the activation of N-hydroxy-N-4-acetylaminobiphenyl by N leads to O acyltransfer. Approximately equal quantities of 4-nitrosobiphenyl and the hydroxamic acid were bound to protein, but far less of the nitroso derivative was incorporated into RNA. Adduct formation of N-hydroxy-N-2-acetylaminofluorene with RNA occurred with retention of the acetyl group and was dependent on the concentration of sulfate in the media. Consequently, reaction of the fluorenyl derivative with RNA probably resulted from conjugation of the hydroxamic acid with sulfate.

Activation of carcinogenic arylhydroxamic acids by human tissues.

Incubation of the carcinogenic arylhydroxamic acids N-hydroxy-N-2-fluorenylacetamide or N-hydroxy-N-4-biphenylacetamide and tRNA with 105,000 times g supernatants of homogenates of human small intestine, liver, or colon led to formation of arylamine-substituted nucleic acid adducts. These data indicated that enzymes of human tissues could activate arylhydroxamic acids by N leads to O acyl transfer. The unstable N-acetoxyarylamines formed by these enzymes reacted spontaneously with the tRNA to give covalently linked adducts with the nucleic acid.

Irradiation-induced adduct formation of RNA with carcinogenic arylamine derivatives.

Radiolysis of N2O-saturated solutions of transfer RNA (tRNA) and the arylacethydroxamic acids, N-hydroxy-N-2-acetylaminofluorene and N-hydroxy-N-4-acetylaminobiphenyl; their corresponding acetamides, 2-acetylaminofluorene and 4-acetylaminofluorene; or the O-glucuronide of N-hydroxy-N-2-acetylaminofluorene resulted in adduct formation of the nucleic acid with these carcinogenic arylamine derivatives. The yield of adducts on irradiation of the arylacethdroxamic acids with tRNA was greater than that for their corresponding acetamides or the O-glucuronide. The fluorenylacethydroxamic acid and acetamide were also more reactive than the biphenyl analogs. Adduct formation resulting from radiolysis of tRNA and the arylacethydroxamic acids or the O-glucuronide proceeded with retention of both the aromatic nucleus and the N-acetyl group. The yields of adducts were much greater for irradiated mixtures than for irradiation of either component alone followed by mixing. Evaluation of the data shows that initial modification of the tRNA or the carcinogen can lead to adduct formation. In the case of primary radical attack of the nucleic acid, it has been shown that short-lived reactive RNA intermediates are responsible for a major fraction of the observed yield of adducts in the irradiated mixtures. Comparative studies showed that irradiation under conditions that favor reaction of oxidizing radicals enhanced formation of the adducts. Oxygen was shown to protect RNA from irradiation-induced binding of the arylacethydroxamine acids due to competition of O2 with the carcinogen for the reactive RNA intermediates.

Synthesis and antimicrobial activity of N-substituted N'-cyano-S-(triorganostannyl)isothioureas.

Six N-substituted N'-cyano-S-(trimethylstannyl)isothioureas were synthesized by the reaction of (trimethylstannyl)cyanamide with various organic isothiocyanates. The IR spectrum of each compound was obtained over the 4000-30-cm(-1) range, and some bands were assigned. The six new compounds and five previously synthesized N-substituted N'-cyano-S-(triphenylstannyl)isothioureas were tested for and were found to exhibit antifungal activity. N-Phenyl-N'-cyano-S-(triphenylstannyl)isothiourea was also investigated for antibacterial activity and was observed to be especially inhibitory toward Gram-positive species. The antimicrobial activity of two compounds was compared to that of the oxygen analogs of these compounds.