Synthetic Transformations of Higher Terpenoids. 42. Synthesis of New 18-Nor-4-(Carboxyethyl)Isopimara-7,15-Diene Derivatives and Study of Their Cytotoxicity on MCF7, U-87 MG and DU 145 Cancer Cell Lines

Abstract

(E)-16-Aryl-substituted derivatives of tricyclic diterpenoids were synthesized by cross-coupling of isopimaric acid derivatives with substituted iodorenes catalyzed by palladium acetate in the presence of silver carbonate. Condensation of (E)-18-nor-4-(carboxyethyl)-16-(2-carboxyethyl)isopimar-7,15-diene dichloride with propargylamine hydrochloride leads to the corresponding dialkine, which readily reacts with diazide in the Cu(I) catalyzed cycloaddition (CuAAC) reaction, with the formation of macroheterocyclic compound containing a pimaran type tricyclic diterpenoid core and 1,2,3-triazole rings in the linker chain. Reaction of in situ prepared (E)-18-nor-16-azido-4-(carboxyethyl)isopimar-7,15-diene acid chloride with propargylamine hydrochloride or an alkynyl-substituted derivative of the protected Gly-Gly dipeptide leads to the corresponding azidoalkynes. The intramolecular CuAAC reaction of azidodipeptidylalkine afforded a macroheterocyclic derivative containing a dipeptide and triazole moiety in the linker chain. The obtained compounds showed higher (compared with the isopimaric acid) cytotoxicity on tumor cells MCF-7 and were less toxic to non-cancer cells than the reference drug doxorubicin. The GI50 value of the most active compound is 6.3 μM, selectivity index 15) (MTT test). The synthesized derivatives of the tricyclic diterpenoid isopimaric acid can be used to develop new antitumor agents.