1. Academic Validation
  2. Preparation of novel ring-A fused azole derivatives of betulin and evaluation of their cytotoxicity

Preparation of novel ring-A fused azole derivatives of betulin and evaluation of their cytotoxicity

  • Eur J Med Chem. 2017 Jan 5:125:629-639. doi: 10.1016/j.ejmech.2016.09.065.
Victoria V Grishko 1 Irina A Tolmacheva 2 Vladimir O Nebogatikov 2 Natalia V Galaiko 2 Alexei V Nazarov 2 Maxim V Dmitriev 3 Irena B Ivshina 4
Affiliations

Affiliations

  • 1 Institute of Technical Chemistry of Ural Branch of the Russian Academy of Sciences, Acad. Korolev St. 3, 614013 Perm, Russia. Electronic address: grishvic@gmail.com.
  • 2 Institute of Technical Chemistry of Ural Branch of the Russian Academy of Sciences, Acad. Korolev St. 3, 614013 Perm, Russia.
  • 3 Perm State National Research University, Bukirev St. 15, 614990 Perm, Russia.
  • 4 Perm State National Research University, Bukirev St. 15, 614990 Perm, Russia; Institute of Ecology and Genetics of Microorganisms, Russian Academy of Sciences, Golev St. 13, 614081 Perm, Russia.
Abstract

An efficient scheme to synthesize novel ring-A fused heterocyclic derivatives of betulin was developed. The starting reaction of this synthesis was one-pot selective Bacterial oxidation of betulin to betulone used as the key compound to synthesize the substituted azoles such as C(2)-C(3)-fused 1,2,3-triazoles, oxazoles and 1,2,4-triazine, as well as C(1)-C(2)-fused isoxazoles. The semi-synthetic compounds were screened for their cytotoxic activity against human Cancer cell lines A549, HCT 116, HEp-2, MS and RD TE32 with use of the photometric MTT assays. Among the tested compounds, N-acetyltriazole of betulin (10) displayed impressive cytotoxic activity with IC50 2.3-7.5 μM against HCT 116, HEp-2, MS and RD TE32 cell lines as well as 3-methyl-4-oxido-1,2,4-triazine-derivative of betulonic acid (12) that was active against HCT 116 and HEp-2 cell lines with IC50 1.4 and 1.5 μM, respectively. Comparative experiments showed triazole (10) to have a lower cytotoxicity to normal epithelial cells, in comparison with compound (12). In accord with the in vivo acute toxicity test, the LD50 of triazole (10) exceeded 600 mg/kg. The ability of the most potent active triazole (10) to trigger apoptotic cell death was explored in the Annexin V-FITC test and by analyzing of Caspase activity and morphological alterations in mitochondria and nuclei of HCT 116 cells.

Keywords

Apoptosis; Azoles; Betulin; Heterocycles; MTT assay; Tumor cells.

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