title: Acyloxymethyl esterification of nodularin-R and microcystin-LA produces inactive protoxins that become reactivated and produce apoptosis inside intact cells.
abstract: 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.
authors.affiliation: Translational Signaling Group, Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, N-5009 Bergen, Norway. Lars.herfindal@biomed.uib.no
authors.forename: Lars
authors.initials: L
authors.lastname: Herfindal
authors.forename: Franciszek
authors.initials: F
authors.lastname: Kasprzykowski
authors.forename: Frank
authors.initials: F
authors.lastname: Schwede
authors.forename: Leszek
authors.initials: L
authors.lastname: Łankiewicz
authors.forename: Kari E
authors.initials: KE
authors.lastname: Fladmark
authors.forename: Joanna
authors.initials: J
authors.lastname: Łukomska
authors.forename: Matti
authors.initials: M
authors.lastname: Wahlsten
authors.forename: Kaarina
authors.initials: K
authors.lastname: Sivonen
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Grzonka
authors.forename: Bernd
authors.initials: B
authors.lastname: Jastorff
authors.forename: Stein Ove
authors.initials: SO
authors.lastname: Døskeland
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003603:Cytotoxins / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D004950:Esterases / Q000378:metabolism; D004951:Esterification; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D052998:Microcystins / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D010658:Phenylglyoxal / Q000737:chemistry; D051381:Rats
chemical_list: D003603:Cytotoxins; D052998:Microcystins; D010456:Peptides, Cyclic; C063998:nodularin; C049865:cyanoginosin-LA; D004950:Esterases; D010658:Phenylglyoxal