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

• Published in: European journal of medicinal chemistry Vol. 185; pp. 111806 - 111823
• Main Authors: Borková, Lucie, Frydrych, Ivo, Jakubcová, Nikola, Adámek, Richard, Lišková, Barbora, Gurská, Soňa, Medvedíková, Martina, Hajdúch, Marián, Urban, Milan
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.01.2020; Elsevier
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biological activity; Cancer; Caspase assay; Cell Proliferation - drug effects; Cells, Cultured; Chemistry, Medicinal; Cytotoxicity; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fibroblasts - drug effects; Heterocycle; Humans; Life Sciences & Biomedicine; Membrane Potential, Mitochondrial - drug effects; Microsomes - chemistry; Microsomes - metabolism; Molecular Structure; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - chemistry; Oleanolic Acid - pharmacology; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Terpenes - chemical synthesis; Terpenes - chemistry; Terpenes - pharmacology; Thiazole; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Triterpene; Triterpenes - chemistry; Triterpenes - pharmacology; Triterpene; Cytotoxicity; Heterocycle; Caspase assay; Thiazole; Biological activity; Apoptosis; Cancer; BETULIN; OLEANANE; URSOLIC ACID; LUPANE; PROFILE; URSANE; CHEMISTRY; PENTACYCLIC TRITERPENOIDS; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111806

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). [Display omitted] •35 New triterpenoids were prepared and characterized, including 30 aminothiazoles.•Their cytotoxicity was evaluated in 8 cancer and 2 non-cancer cell lines.•Pharmacological parameters were found for 7 selected compounds.•4 Derivatives were proven to selectively cause apoptosis via intrinsic pathway.•Most effective compounds (5m and 7b) were selected for further development.