Tagitinin C, a Sesquiterpene Lactone, and Derivatives as Proteasome Inhibitors

Abstract

Tagitinin C, a germacranolide isolated from Tithonia diversifolia, is shown to be an inhibitor of the proteasome pathway. It is, however, a particularly unstable molecule, sensitive to acids, bases, nucleophiles, and light. Herein, a series of modifications aimed at improving the chemical and biological properties of the molecule is described. This study particularly focuses on isobutyrate chain replacement with other esters or ethers. The key steps are the cross-conjugated dienone reactivity neutralization by reduction and methylene lactone protection with morpholine or imidazole. Selective saponification of the isobutyrate is also achieved with crude pig liver esterase, leading to tagitinol C in moderate yield. Heliangine from the Jerusalem artichoke (Helianthus tuberosus) and hydroxylated derivatives of tagitinin C from the common sunflower (Helianthus annuus), two abundant field crops, constitute alternative sources of germacranolide derivatives not accessible from tagitinin C. Some esters are more potent than the lead compound, whereas the di-ethers display higher activity levels, probably due to better in vivo stability.