Thioterpenoids of Mentane Series: Synthesis, Antioxidant and Membrane Protective Activity

In the studies of various kinds of biological activity of sulphur-containing monoterpenoids, we previously revealed a practically promising leading compound, the product of the reaction of limonene-(+)-1,2-oxide with methylmercaptoacetate. In the present work, investigation of the antioxidant and membrane-protecting activity of this leading compound is presented in comparison with the starting structures for its synthesis: limonene and limonene-1,2-oxide. For the studies of antioxidant activity, erythrocytes from the blood of laboratory animals were used as a cell test system, and a heterogeneous substrate based on the brain homogenate of laboratory animals was the non-cellular test system. Membrane-protective activity was studied under the conditions of Н2О2-induced hemolysis and with oxidative stress induction by 2,2′-azobis-(2-amidinopropane)dihydrochloride. It is shown that all the three compounds exhibit statistically significant antioxidant and membrane-protective activity in both test systems. The most active compound is the leading one, thioterpenoid with the methylmercaptoacetate fragment. In order to expand the synthesis possibilities of monoterpenes of menthane series in thiating reactions, and develop the approach to the synthesis of new potentially bioactive thioterpenoids, the pharmacophoric methylmercaptoacetate fragment was introduced into the structure of limonene dioxide and carvone. The reaction of limonene with methylmercaptoacetate in a basic medium resulted in obtaining a bicyclic product of intramolecular cyclisation participated by the OH group at isopropenyl fragment. The reaction of carvone with methylmercaptoacetate under acid catalysis occurred regioselectively, with the formation of terpene sulphide at the endo-cyclic double bond. The crystal structures of the two latter terpene sulphides were studied by X-ray diffraction. Both thioterpenoids in the crystals under investigation are represented by only one enantiomer.