Synthesis, evaluation of cytotoxicity, and antimicrobial activity of A-azepano- and A-seco-3-amino-C28-aminolupanes

Abstract

A series of new C28-amino-lupanes bearing A-azepano- and A-seco-3-amino-fragments was synthesized from 3,28-dioximino-betulin and evaluated for cytotoxicity toward the NCI-60 cancer cell line panel and antimicrobial activity against key ESKAPE pathogens. A-azepano-28-amino-betulin exhibited remarkable activities with GI50 ranging from 1.16 to 2.27 μM against all panel with the highest activity toward leukemia, colon cancer, non-small cell lung cancer and breast cancer. The replacement of the hydroxyl group at C28 in the structure of azepanobetulin to the amino group did not show a strong effect on the cytotoxic activity. Both compounds were ∼5 and ∼4 times more active than doxorubicin against colon cancer HCT-15 and ovarian cancer NCI/ADR-RES cell lines, thus these A-azepano-lupane triterpenoids are the promising agents for future anticancer drug development. The ability of A-azepanobetulin to inhibit cell growth may be associated with its cytostatic effect, which, depending on the cell line, is associated with the arrest either S or G1 phase of cell cycle. 3-Amino-3,4-seco-28-amino-lup-4(23),20(29)-dien exhibited significant bacteriostatic effect against methicillin-resistant Staphylococcus aureus (MIC ≤ 0.25 μg/mL) that exceeds the effect of the clinically used antibiotic vancomycin.

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Acknowledgements

This work was supported by Federal programs (N AAAA-A20-120012090023-8, AAAA-A20-120012090029-0, and AAAA-A17-117011910028-7). The synthesis of compounds 2, 4, 5, and 9-11 and evaluation of their biological activity were supported by the Russian Foundation for Basic Research (project no. 18-33-00364 for TVL). We thank National Cancer Institute for the screening of cytotoxicity of compounds 211. The antimicrobial screening was performed by CO-ADD (The Community for Antimicrobial Drug Discovery) and funded by the Wellcome Trust (UK) and The University of Queensland (Australia).

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Correspondence to Oxana B. Kazakova.

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Kazakova, O.B., Lopatina, T.V., Baikova, I.P. et al. Synthesis, evaluation of cytotoxicity, and antimicrobial activity of A-azepano- and A-seco-3-amino-C28-aminolupanes. Med Chem Res 29, 1507–1519 (2020). https://doi.org/10.1007/s00044-020-02577-6

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Keywords

  • Triterpenoids
  • Lupane
  • Betulin
  • Beckmann rearrangement
  • Lactame
  • Azepane
  • Cytotoxicity
  • Antimicrobial activity