On the Mechanism of Action of the Cytostatic Drug Anguidine and of the Immunosuppressive Agent Ovalicin, two Sesquiterpenes from Fungi1

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Abstract
The sesquiterpene betainyl–anguidine and the structurally related verrucarin A at the low concentration of 10–8 mol/l inhibit protein synthesis in lymphocytes from mouse spleen rapidly after addition to the cell culture. DNA synthesis is blocked at similarly low concentrations whereas RNA synthesis is much less reduced. The following observations support the notion that DNA synthesis is blocked via inhibition of protein synthesis: (i) DNA synthesis in a cell–free system is not reduced by the drug; (ii) in cell culture protein synthesis is inhibited more rapidly and at lower concentrations than DNA synthesis; (iii) inhibitors of protein synthesis such as cycloheximide or puromycin are similar to betainyl–anguidine in their action on lymphocytes whereas specific inhibitors of DNA synthesis such as cytosine arabinoside or hydroxyurea only partially reduce protein synthesis in lymphocytes. The sesquiterpene ovalicin at a concentration of 10–10 mol/1 acts as a very potent inhibitor of DNA synthesis in proliferating lymphocytes and in lymphoma cells. RNA and pro.tein synthesis are only weakly affected. The following observations support the conclusion that DNA synthesis is blocked only indirectly: (i) DNA synthesis in a cell–free system is not reduced by ovalicin; (ii) a cell–free system for DNA synthesis prepared from ovalicin–treated lymphocytes shows an impaired synthetic activity; (iii) in cell culture the action of ovalicin is not immediate and requires a 8–15 hour period of incubation.

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