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. Epub 2018 Oct 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Esterification
  • HCT116 Cells
  • Humans
  • Models, Molecular
  • Neoplasms / drug therapy
  • Triterpenes / chemical synthesis
  • Triterpenes / chemistry*
  • Triterpenes / pharmacology*

Substances

  • Antineoplastic Agents
  • Triterpenes