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

Abstract

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.