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

Abstract

Tagitinin C, a germacranolide, isolated from Tithonia diversifolia was shown to have an interesting level of activity on the proteasome pathway. It is however a particularly unstable molecule, sensitive to acids, bases, nucleophiles, and light. This article describes a series of modifications aimed at improving the chemical and biological properties of the molecule and securing a solid industrial property. This study particularly focuses on the isobutyrate chain replacement by other esters or ethers. The key steps were the cross-conjugated dienone reactivity neutralization by reduction and the methylene lactone protection with morpholine or imidazole. Selective saponification of the isobutyrate was also achieved with crude pig liver esterase leading to tagitinol C with a 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, constituted alternative sources of germacranolide derivatives not accessible from tagitinin C. Some esters were more potent than the lead compound, whereas the di-ethers displayed higher activity levels, probably due to a better in vivo stability.