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Mutagenicity Experiments on Agroclavines, New Natural Antineoplastic Compounds¹

Institut für Toxikologie der Universität Mainz, Obere Zahlbacher Strasse 67, [H. G., F. O.], Fachbereich Pharmazie der Universität Mainz, Saarstrasse 21, [E. E., H. P., C. B.] D-6500 Mainz, Federal Republic of Germany

Agroclavine, an alkaloid produced by some species of fungi and dicotyledon plants, and its 1-alkylated derivatives are potentially useful as antineoplastic drugs, since they exert potent and selective cytostatic effects. In the present study, we have investigated agroclavine and its 1-propyl and 1-pentyl derivatives for mutagenicity. The genetic end point studied was the reversion of strains of Salmonella typhimurium (TA 100, TA 98, TA 1537) and Escherichia coli (WP2.uvrA), auxotrophic for histidine and tryptophan, respectively. The compounds were tested directly and in the presence of a mammalian xenobiotic-metabolizing system. In the direct test, agroclavine and the two alkylated derivatives examined exhibited substantial bacteriotoxicity but no mutagenicity. Addition of NADPH-fortified postmitochondrial supernatant fraction of rat liver homogenate led to a clear-cut decrease in bacteriotoxicity and to the formation of mutagenic products. Each compound was effective in all three strains of S. typhimurium used. In E. coli only spurious effects were seen. 1-Pentylagroclavine, the most hydrophobic compound in the series, was the strongest mutagen. Agroclavine, the least hydrophobic compound, was the weakest. The mutagenic potencies and efficacies of all these test compounds were much weaker than those of the positive controls, which were known mutagens and carcinogens. Moreover, the differential effect of metabolism by liver enzymes demonstrates that the toxicity and mutagenicity of agroclavine and its derivatives are caused by different chemical species. Hence, it may be possible to develop derivatives that are cytotoxic but not mutagenic.

¹ This study was supported by the Deutsche Forschungsgemeinschaft (SFB 302) and the Deutsche Krebshilfe e.V.-Dr. Mildred-Scheel-Stiftung/Deutsche Stiftung für Krebsforschung. No. 4 of the series "Clavines as Antitumor Agents"; for No. 3 see Ref. 9.

² To whom requests for reprints should be addressed.

Received 3/ 3/86. Revised 12/18/86. Accepted 1/ 7/87.