Synthesis and cytotoxicity of water-soluble ambrosin prodrug candidates.

Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.

Journal of medicinal chemistry 1995 Aug 18

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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 alpha,beta-unsaturated ketone and alpha-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-sulfinic acid analog had low activity. Biological evaluation of several ambrosin analogs with reduced and/or isomerized alpha,beta-unsaturated ketone and alpha-methylene lactone moieties demonstrated the importance of both of these functional groups for biological activity.

Citation

E Hejchman, R D Haugwitz, M Cushman. Synthesis and cytotoxicity of water-soluble ambrosin prodrug candidates. Journal of medicinal chemistry. 1995 Aug 18;38(17):3407-10