Cytotoxicity of Sesquiterpene Lactones1

The recent discovery and structure elucidation of approximately 100 new sesquiterpene lactones during a systematic study of Artemisia and other genera of the family of Compositae in our laboratory (16) have provided the opportunity for further investigations on the potential of these sesquiterpene lactones as new therapeutic agents. Much of the earlier study on sesquiterpene lactones for medicinal purposes has concentrated mainly on santonin (I), a santanolide, and its derivatives, which are well known as important anthelmintic and ascaricidal agents (21). With the increased activity in recent years in searching for tumor inhibitors or cytotoxic principles from a random screening of plant sources, a program supported in the United States and in many other parts of the world by the Cancer Chemotherapy National Service Center, National Cancer Institute, NIH, many sesquiterpene lactones bearing an a-methylene-7-lactone grouping have occasionally been isolated and shown to contain significant antitumor or cytotoxic activity. These include the germacranolides, elephantin, elephantopin (see Ref. 26 and the references therein), costunolide, and tulipinolide (10); the guaianolides, gaillardin (see Ref. 27 and the references therein), euparotin acetate, and its companions (see Ref. 26 and the references therein), the pseudoguaianolide, damsin (11); and the elemanolide, vernolepin (see Ref. 26 and the references therein). Although the structural requirements for the antitumor or cytotoxic activity of some of the above sesquiterpene lactones have been postulated (see Ref. 31 and the references therein), and attempts have been made to explain their mechanism of action (see Refs. 26 and 31 and the references therein), there has been a need for further study of other structural types of the sesquiterpene lactones, such as santanolides and