Halogenation of Sesquiterpene γ-Lactone Molecules: New Compounds, Structure and Biological Activity

This article presents the results of halogenation studies on seven sesquiterpene γ-lactones readily obtainable from plant material: the germacranolide argolide, the eudesmanolide isoalantolactone, and the guaianolides arglabin, achillin, grossheimin, grossmisin, and leucomisine. Sesquiterpene γ-lactones occurring in plants of the Asteraceae (Compositae) family constitute an important class of terpenoids, among which chlorine-containing compounds are distinguished by pronounced biological activity. The aim of this study was to synthesize new biologically active halogen-containing derivatives of sesquiterpene γ-lactones. Thirty-four new halogen-containing compounds were synthesized by substitution and addition reactions, taking into account the structural features and reactive sites of the parent substrates, including the α-methylene-γ-lactone moiety, hydroxy and keto groups, exocyclic double bonds, and cyclopentadienone fragments. The structures of all synthesized compounds were established from physicochemical constants and spectroscopic data (IR, UV, 1H NMR, 13C NMR, COSY, NOESY, and COLOC). X-ray diffraction analysis was used for definitive structural assignment of the (E)- and (Z)-isomers. Biological screening demonstrated pronounced cytotoxic, antitumour, antifungal, and antimicrobial activities for several of the halogen-containing sesquiterpene lactones. Against Artemia salina (Linnaeus, 1758) larvae, the dichlorocarbene derivative of arglabin was 32.7-fold more cytotoxic than the parent arglabin, whereas 1α,10β-dichloro-14α-methoxyachillin was 2.6-fold more active than achillin.