Synthesis, modification, and cytotoxic evaluation of 2,3-secotriterpenic β-ketoesters

  • Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3752-3760. doi: 10.1016/j.bmcl.2018.10.014.
Daria V Eroshenko  1 ,  Gulnaz F Krainova  1 ,  Anastasia V Konysheva  1 ,  Maksim V Dmitriev  2 ,  Victoria V Grishko  3
Affiliations
  • 1. Institute of Technical Chemistry of the Ural Branch of the Russian Academy of Sciences, Perm Federal Scientific Centre, Acad. Korolev St. 3, 614013 Perm, Russia.
  • 2. Perm State National Research University, Bukirev St. 15, 614990 Perm, Russia.
  • 3. Institute of Technical Chemistry of the Ural Branch of the Russian Academy of Sciences, Perm Federal Scientific Centre, Acad. Korolev St. 3, 614013 Perm, Russia. Electronic address: [email protected].
PMID: 30340899 DOI: 10.1016/j.bmcl.2018.10.014
Abstract

A set of β-ketoesters was synthesized from 2,3-seco-18αH-oleanane and 2,3-secolupane bromomethyl ketones. Additionally, hydroxy derivatives with the A-seco- or five-membered A ring were obtained as a result of the reduction or of alkaline hydrolysis of acetic acid β-ketoesters 4, 9. Cytotoxic screening revealed the compound 4 with marked activity (IC50 3.07-3.61 µM) against the HCT 116, MS, RD TE32 Cancer cells. The studies of the cytotoxic mechanism enabled elucidating the fact that treatment of the HCT 116 cells with compound 4 for 18 h leads to induction of Apoptosis in a dose-dependent manner. This observation was confirmed by registration of chromatin condensation, by the fluorescence increased during Annexin V-FITC staining, and by appearance of a sub-G0 peak in the cell cycle analysis with DAPI. Compound 4 also inhibited migration of Cancer cells in the wound healing assay.

Keywords
A-secotriterpenoids; Apoptosis; Cancer cells; MTT assay; Oxo-nitrile cyclization; β-Ketoester.