Relation of toxicity and conformation of phallotoxins as revealed by optical rotatory dispersion studies.

Abstract

Natural variants and chemically modified derivatives of phalloidin have been found or prepared which show all degrees of toxicity. High toxicity persists if only three of the side chains are modified. Acetylation of two of the four OH groups of phalloidin leads to less toxic products, the triacetyl derivative is nontoxic. On tosylation toxicity disappeared after reaction of only two OH groups. Alkylation of the indole nitrogen leads to equally or less toxic (N‐methy), ‐ethyl, carbamoylmethyl, ‐tert.butyl) or nontoxic (N‐propyl, ‐pentyl) products. Toxicity is also completely absent if only one of the two rings of the molecule is intact.In optical rotatory dispersion spectra all of the toxic compounds show in aqueous solution two cotton effects centered around 300 nm and 248 nm, whereas in nearly all of the nontoxic derivatives at least one of the effects is missing. Triacetylphalloidin and tribromophalloidin, both nontoxic, also exhibit “toxic” curves in water. Their conformation, however, changes on going to organic solvents like methanol or acetonitril as observed by optical rotatory dispersion studies. Thus, stability of the “aqueous” conformation in a lipophilic environment is apparently the second prerequisite for a toxic action of phallopeptides.