Acyloxymethyl esterification of nodularin-R and microcystin-LA produces inactive protoxins that become reactivated and produce apoptosis inside intact cells.

We report the esterification of the carboxyl groups of the cyclic peptide toxins nodularin-R and microcystin-LA to produce stable diacetoxymethyl and dipropionyloxymethyl ester derivatives. The derivatives had no activity but were reactivated upon esterase treatment. When injected into cells, the acyloxymethyl moieties were cleaved off and apoptosis induced. Linking the acyloxymethyl-ester moiety of these potent toxins to carriers destined for endocytosis paves the way for selective apoptosis induction in target (e.g., cancer) cells.