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Synthetic modification and cytotoxic evaluation of 2-cyano-3,4-secotriterpenic methylketones

Alexey V. Nazarov, Irina A. Tolmacheva, Anastasia E. Zhukova, and Victoria V. Grishko

Institute of Technical Chemistry, Perm Federal Scientific Centre, Ural Branch of the Russian Academy of Sciences, Perm, Russia

 

E-mail: grishvic@gmail.com

Abstract: Triterpenic methylketones, known earlier and obtainable as a result of oxidative transformation of double bond(s) in 2-cyano-3,4-secoderivatives of the lupane and 18αH-oleanane types, can be regarded as promising intermediates for synthetic transformation. This study has demonstrated the acid-catalyzed α-bromination of methylketones as capable of providing a series of various bromine-substituted ketones with different degrees of halogenation, as well as the 3,23,24-trinor-3,4-seco-18αH-oleanane acid resulting from the tribromoketone by elimination of a bromoform fragment under the same conditions. The 3,4-seco-acid ester derivative was then transformed, via the base-catalyzed intramolecular nitrile anion cyclization, to a derivative with the ketonitrile fragment in the five-membered A cycle, dehydrogenation of which afforded a cyano enone derivative. With use of the base catalysis, the 3,4-secotriterpenic bromohydrins synthesized via stereoselective reduction of 18αH-oleanane mono- and dibromoketones were transformed to C(4) epimeric terminal 4,23-epoxides. According to cytotoxic screening of the synthesized compounds, the bromoketones showed the most pronounced cytotoxic effect, whereas their derivatives partially or completely lost their cytotoxicity against the tumor cell lines under MTT test. The IC50 values characterizing the proliferation inhibition of HCT116, MS, RD TE32, and PC3 cells for the most active 2-cyano-24,24-dibromo-19β,28-epoxy-3,4-seco-3,23-dinor-18αH-olean-4-one 7 spanned the range 2.06–7.51 μM.

Keywords: 3,4-secotriterpenoids ; Methylketones ; Nitrile anion cyclization ; Cytotoxicity ; MTT test ; SAR 

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-019-00729-6

 

Chemical Papers 73 (7) 1767–1775 (2019)

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