Synthesis and cytotoxicity of water-soluble ambrosin prodrug candidates.
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.
Hejchman
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E
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Haugwitz
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RD
Cushman
M
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045789:Sesquiterpenes, Guaiane; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011355:Prodrugs; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; C010675:ambrosin