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

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(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.

作者简介

M. Gromova

Novosibirsk State Pedagogical University (NSPU),; Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences

Email: schultz@nioch.nsc.ru
Russia, 630126, Novosibirsk, ul. Vilyuskaja 28; Russia, 630090, Novosibirsk, prosp. Akad. Lavrentyevа 9

Y. Kharitonov

Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences

Email: schultz@nioch.nsc.ru
Russia, 630090, Novosibirsk, prosp. Akad. Lavrentyevа 9

Т. Rybalova

Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences

Email: schultz@nioch.nsc.ru
Russia, 630090, Novosibirsk, prosp. Akad. Lavrentyevа 9

V. Larionov

Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences (INEOS RAS)

Email: schultz@nioch.nsc.ru
Russia, 119334, Moscow, ul. Vavilova 28

T. Golubeva

The Federal Research Center Institute of Cytology and Genetics SB RAS (ICG SB RAS)

Email: schultz@nioch.nsc.ru
Russia, 630090, Novosibirsk, prosp. Akad. Lavrentyevа 9

E. Shults

Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences

Email: schultz@nioch.nsc.ru
Russia, 630090, Novosibirsk, prosp. Akad. Lavrentyevа 9

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版权所有 © М.А. Громова, Ю.В. Харитонов, Т.В. Рыбалова, В.А. Ларионов, Т.С. Голубева, Э.Э. Шульц, 2023

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