Synthesis and cytotoxicity of water-soluble ambrosin prodrug candidates

Article abstract of DOI:10.1021/jm00017a025

The potential therapeutic application of the naturally occurring, cytotoxic pseudoguaianolide sesquiterpene lactone ambrosin is limited by its aqueous insolubility. A number of water-soluble ambrosin derivatives have therefore been prepared for potential use as prodrugs. Michael addition of several secondary amines to both the α,β-unsaturated ketone and α- methylene lactone moieties of ambrosin afforded tertiary amine diadducts that were converted to water-soluble hydrochloride salts. The salt of the bis- piperidine adduct proved to be the most potent, producing cytotoxic activity only slightly less potent than that of ambrosin itself in a variety of human cancer cell cultures. The sodium salt of the bis-sulfonic acid derivative of ambrosin was inactive, while the sodium salt of the bis-sulfonic acid analog had low activity. Biological evaluation of several ambrosin analogs with reduced and/or isomerized α,β-unsaturated ketone and α-methylene lactone moieties demonstrated the importance of both of these functional groups for biological activity.