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

Gromova, M.A.; Kharitonov, Y.V.; Rybalova, Т.V.; Larionov, V.А.; Golubeva, T.S.; Shults, E.E.

Авторы: Gromova M.A., Kharitonov Y.V., Rybalova Т.V., Larionov V.А., Golubeva T.S., Shults E.E.
Журнал: Russian Journal of Bioorganic Chemistry
Том: 49
Год издания: 2023
Издательство: Maik Nauka/Interperiodica Publishing
Местоположение издательства: Russian Federation
Первая страница: 1076
Последняя страница: 1088
DOI: 10.1134/S1068162023050151
Аннотация: (E)-16-Aryl-substituted tricyclic diterpenoids were synthesized by the cross coupling of isopimaric acid derivatives with substituted iodoarenes, catalyzed by palladium acetate in the presence of silver carbonate. The condensation of the resulting (E)-18-nor-4-(2-carboxyethyl)-16-(2-carboxyphenyl)isopimara-7,15-diene dichloride with propargylamine hydrochloride leads to the corresponding dialkyne, which readily enters a Cu(I)-catalyzed cycloaddition with 1,2-bis(2-azidoethoxy)ethane. The main product of this reaction is a macroheterocyclic compound containing a pimaran type tricyclic diterpenoid fragment and 1,2,3-triazole rings in the linker chain. The reaction of the in situ prepared (E)-18-nor-16-azido-4-(2-carboxyethyl)isopimara-7,15-dienoic acid chloride with propargylamine hydrochloride or alkynyl-substituted derivative of the protected Gly–Gly dipeptide gave the corresponding azidoalkynes. The intramolecular CuAAC reaction of azidodipeptidylalkyne resulted in the preparation of a macroheterocyclic derivative containing dipeptide and triazole fragments in the linker chain. The synthesized compounds showed a higher (compared to isopimaric acid) cytotoxicity on MCF7, U-87 MG, and DU 145 cancer cell models and were less toxic to non-cancer cells than the reference drug Doxorubicin. The GI50 of the most active compound was 6.3 μM (selectivity index >15) (MTT test). The synthesized derivatives of the tricyclic diterpenoid isopimaric acid can be used to develop new anticancer agents.
Добавил в систему: Ларионов Владимир Анатольевич

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Synthetic Transformations of Higher Terpenoids. 42. Synthesis of New 18-nor-4-(Carboxyethyl)isopimara-7,15-diene Derivatives and Their Cytotoxicity Assessment on MCF7, U-87 MG, and DU 145 Cancer Cell Linesстатья Исследовательская статья

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