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  3. Synthesis and biological evaluation of triterpenoid thiazoles derived from betulonic acid, dihydrobetulonic acid, and ursonic acid

Synthesis and biological evaluation of triterpenoid thiazoles derived from betulonic acid, dihydrobetulonic acid, and ursonic acid

  • Eur J Med Chem. 2020 Jan 1;185:111806. doi: 10.1016/j.ejmech.2019.111806.
Lucie Borková 1,  Ivo Frydrych 2,  Nikola Jakubcová 3,  Richard Adámek 3,  Barbora Lišková 2,  Soňa Gurská 2,  Martina Medvedíková 2,  Marián Hajdúch 2,  Milan Urban 4
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, Faculty of Science, Palacky University in Olomouc, 17. listopadu 1192/12, 771 46, Olomouc, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hněvotínská 5, 779 00, Olomouc, Czech Republic.
  • 2 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hněvotínská 5, 779 00, Olomouc, Czech Republic.
  • 3 Department of Organic Chemistry, Faculty of Science, Palacky University in Olomouc, 17. listopadu 1192/12, 771 46, Olomouc, Czech Republic.
  • 4 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University in Olomouc, Hněvotínská 5, 779 00, Olomouc, Czech Republic. Electronic address: milan.urban@upol.cz.
PMID: 31677446 DOI: 10.1016/j.ejmech.2019.111806
Abstract

In this work, 35 new derivatives of betulonic, dihydrobetulonic and ursonic acid were prepared including 30 aminothiazoles and all of them were tested for their in vitro cytotoxic activity in eight Cancer cell lines and two non-cancer fibroblasts. Compounds with the IC50 below 5 μM in CCRF-CEM cells and low toxicity in non-cancer fibroblasts (4m, 5c, 5m, 6c, 6m, 7b, and 7c) were further subjected to tests of pharmacological parameters yielding the final set for advanced biological evaluation (4m, 5m, 6m, and 7b). It was proved by several methods, that all of them trigger Apoptosis via the intrinsic pathway and derivatives 5m and 7b are the most effective (IC50 2.4 μM and 3.6 μM). They are the best candidates to become potentially new Anticancer drugs and will be subjected to in vivo tests in mice. In addition, compounds 6b and 6c deserve more attention because their activity is not limited only to chemosensitive CCRF-CEM cell line. Specifically, compound 6b is highly active against K562 leukemic cell line (0.7 μM) and its IC50 activity in colon Cancer HCT116 cell line is 1.0 μM. Compound 6c is active in both normal K562 and resistant K562-TAX cell lines (IC50 3.4 μM and 5.4 μM) and both colon Cancer cell lines (HCT116 and HCT116p53-/-, IC50 3.5 μM and 3.4 μM).

Keywords

Apoptosis; Biological activity; Cancer; Caspase assay; Cytotoxicity; Heterocycle; Thiazole; Triterpene.

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