Structure-activity relationships of illudins: analogs with improved therapeutic index.

Illudin S and M are extremely toxic sesquiterpenes produced by Omphalotus illudens. At low pH they behave as bifunctional alkylating agents, but at physiological pH they do not react with oxygen or nitrogen nucleophiles. Illudins react spontaneously with sulfur nucleophiles, glutathione or cysteine, at or slightly below pH 7, and toxicity to HL 60 cells can be modulated by altering glutathione levels in cells. Analogs of illudin M, e.g. the deoxy and, particularly, the dehydro derivatives, are less reactive to thiols and correspondingly less toxic to HL 60 cells than the parent compound. Dehydroilludin M has been found to be quite effective at inhibiting tumor growth in vivo at doses well tolerated by athymic nude mice.