Synthetic Transformations of Higher Terpenoids. 46. Synthesis and Cytotoxic Properties of 16-(1,2,4-Oxadiazolyl)lambertianic Acid Derivatives

Abstract Objective: Design, synthesis and cytoxic properties of a series of new derivatives of lambertianic acid with 1,2,4-oxadiazole substituent in the Furan ring and amido function at C4 position of the labdane core are presented. Methods: The three step formation of original lambertianic acid nitrile and its reaction with hydroxylamine hydrochloride followed by reaction of diterpenoid 16-amidooxime with activated carboxylic acids or a wide variety of their derivatives and cyclodehydration was used for the preparation of 16-(5-substituted-1,2,4-oxadiazolyl)lambertianic acid derivatives. The reaction of in situ generated oxadiazolyl modified lambertianic acid chloroanhydrides with hydroxylamine hydrochloride, hydrochloride of glycyne methyl ester or morpholine was used for selective modification of the diterpenoids in the C4 position. The screening —itro was used for studying the cytotoxicity of new compounds (MTT test). Results and Discussion: The obtained diterpenoid-type 1,2,4-oxadiazoles include compounds with phenyl, 4-fluoro-, 4-methyl-, 4-methoxy-, 3,4,5-trimethoxy-, 2-amino-, 3-amino- and 4-aminophenyl substituents, methyl, trifluoromethyl, tert-butyl and vinyl groups and also with a fragment of shikimic acid. Conclusions: We demonstrated that the introduction of a 1,2,4-oxadiazole substituent into the furan cycle of lambertianic acid, as well as the subsequent modification of the carboxyl group with the introduction of an oxime function, can significantly increase the cytotoxic effect against human MCF7 tumor cells. The results confirm the potential of targeted modification of the plant diterpenoid lambertianic acid for the creation of selective antitumor agents.