The presence of an a-methylene-7-lactone is essential for significant cytotoxic activity among the sesquiterpene lactones. The biological activity is enhanced by the presence of certain additional ,/3-unsaturated carbonyl functions. In addition, the activity of these compounds increases with increasing lipophilicity, but does not appear to correlate with reactivity toward cysteine. Those sesquiterpenes with demonstrated in vivo antitumor activity have common features which set them apart from the majority of the sesquiterpene lactones.A number of significantly cytotoxic sesquiterpene lactones have been isolated during the course of a continuing search for antitumor agents from plant sources.3 Despite the common occurrence of cytotoxic activity and, to a lesser extent, in vivo antitumor activity, this class of compounds has not been subjected to a systematic study of structure-activity relationships. The great structural diversity of these compounds (Chart I) precluded the determination of most of the free energy parameters required for a rigorous Hansch analysis. Other complicating factors, such as solubility difficulties in solvents used for the biological assay and biological variations in the responses, have been noted previously.4 In spite of these limitations, we felt that structure-activity relationship studies of these compounds should reveal general relationships of value to any further biological study in the area of sesquiterpene lactones.Using the data available at the time, Hartwell and Abbott4 surveyed the structural variety of the cytotoxic sesquiterpene lactones and attempted a statistical treatment of the structure-activity problem. As they noted, the small number of examples available made it difficult to arrive at definitive conclusions. It was noted, however, that all the cytotoxic sesquiterpenes were lactones, of which all but one were ,/3-unsaturated, and that the

Communicationsproposal might invoke a [T2 + r2] intramolecular cyclization to 15 which by suitable hydrogen shift and bond reorganization is transformed into 8.18

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Maytansine, at 6x10(-8)M, irreversibly inhibits cell division in eggs of sea urchins and clams. It causes the disappearance of a mitotic apparatus or prevents one from forming if added at early stages. Maytansine does not affect formation of the mitotic organizing center but does inhibit in vitro polymerization of tubulin. Maytansine and vincristine inhibit in vitro polymerization of tubulin at about the same concentrations, but vincristine is about 100 times less effective as an inhibitor of cleavage in marine eggs.

Thiols are the most reactive nucleophilic reagents among the biological models investigated. They undergo "Michael-type" addition to the polyfunctional sesquiterpene lactones. The rapid rates of reaction with L-cysteine were measured and the reaction products were characterized. Each addition of thiol successively decreased the cytotoxicity of the adducts formed.

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Extracts of Euphorbia esula L. and Croton tiglium L., two members of the Euphorbiaceae which have been used widely in folk medicine for treating cancers, showed antileukemic activity against the P-388 lymphocytic leukemia in mice. Systematic fractionation of the extract of Euphorbia esula L. led to characterization of a major antileukemic component as the new diterpenoid diester, ingenol 3,20-dibenzoate. Similar fractionation of Croton oil led to characterization of phorbol 12-tiglate 13-decanoate as an active principle.