Synthesis of New Dihydroquinopimaric Acid Analogs with Nitrile Groups as Apoptosis-Inducing Anticancer Agents

Author(s):

Elena V. Tretyakova*, Elena V. Salimova, Lyudmila V. Parfenova, Milyausha M. Yunusbaeva, Lilya U. Dzhemileva, Vladimir A. D’yakonov and Usein M. Dzhemilev   Pages 1172 - 1183 ( 12 )

Abstract:

<P>Background: Cyan-containing compounds are of great interest as potential anticancer agents. Terpenoids can severe as a natural matrix for the development of promising derivatives with antitumor activity. </P><P> Methods: The 2-cyanoethoxy methyl dihydroquinopimarate derivatives (5-9) were synthesized by the reaction of the intermediates (1-4) with acrylonitrile in the presence of alkali (30% KOH solution) using triethylbenzylammonium chloride. The cytotoxicity evaluation was carried out according to the National Cancer Institute (NCI) Protocol, while apoptosis was studied by flow cytometric analysis of Annexin V and 7-aminoactinomycin D staining and cell cycle was analyzed using the method of propidium iodide staining. </P><P> Results: Synthesis of new dihydroquinopimaric acid derivatives with nitrile groups was carried out. The obtained cyanoethyl derivatives were converted into tetrazole, amine, oxadiazole and amidoxime analogs. The primary screening for antitumor activity showed the highest cytotoxic potency of the cyanoethyl-substituted compounds. The introduction of cyanoethyl groups at C-1, C-4 and C-1, C-4, C-20 positions of dihydroquinopimaric acid methyl ester provided antiproliferative effect towards the Jurkat, K562, U937, and HeLa tumor cell cultures (CC50=0.045-0.154μM). These nitrile derivatives are effective inducers of tumor cell apoptosis affecting the S and G2 phases of the cell cycle in a dose-dependent manner. </P><P> Conclusion: The cyanoethyl analogs of dihydroquinopimaric acid reported herein are apoptosis inducers and cytotoxic agents. These findings will be useful for the further design of more potent cytotoxic agents based on natural terpenes.</P>

Keywords:

Abietane diterpenoids, levopimaric acid, diene adduct, dihydroquinopimaric acid, nitriles, tetrazoles, amines, oxadiazoles, amidoximes, anticancer activity, cell cycle, apoptosis.

Affiliation:

Institute of Petrochemistry and Catalysis of Russian Academy of Sciences, 141 Prospekt Oktyabrya, Ufa 450075, Institute of Petrochemistry and Catalysis of Russian Academy of Sciences, 141 Prospekt Oktyabrya, Ufa 450075, Institute of Petrochemistry and Catalysis of Russian Academy of Sciences, 141 Prospekt Oktyabrya, Ufa 450075, Institute of Petrochemistry and Catalysis of Russian Academy of Sciences, 141 Prospekt Oktyabrya, Ufa 450075, Institute of Petrochemistry and Catalysis of Russian Academy of Sciences, 141 Prospekt Oktyabrya, Ufa 450075, Institute of Petrochemistry and Catalysis of Russian Academy of Sciences, 141 Prospekt Oktyabrya, Ufa 450075, Institute of Petrochemistry and Catalysis of Russian Academy of Sciences, 141 Prospekt Oktyabrya, Ufa 450075

Graphical Abstract:

Read Full-Text article