Selective cytotoxicity of ent‐kaurene diterpenoids isolated from Baccharis lateralis and Baccharis retusa (Asteraceae)

• Published in: Archiv der Pharmazie (Weinheim) 2022-08, Vol.355 (8), p.e2200083-n/a
• Main Authors: Silva, Matheus L., Oliveira, Cyntia S., dos Santos, Wagner J. O., Oliveira, Vani X., Antar, Guilherme M., Lago, João H. G., Cerchiaro, Giselle
• Format: Article
• Language: English
• Subjects: Breast cancer; Cancer; Cytotoxicity; ent‐kaurenoic diterpenoids; in silico ADME
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202200083

This study presents the cytotoxic activity evaluation of the natural diterpenes ent‐kaurenoic acid (1) and its 15β‐hydroxy (2), 15β‐senecioyloxy (3), and 15β‐tiglinoyloxy (4) derivatives, isolated from Brazilian native plants, Baccharis retusa and B. lateralis (Asteraceae). Using the MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) colorimetric assay, it was observed that compound 1 displayed in vitro activity towards the aggressive MDA‐MB‐231 adenocarcinoma cell line and reduced toxicity against MCF‐10A nontumorigenic epithelial cells, indicating expressive selectivity. On the contrary, compounds 2–4 exhibited reduced toxicity and selectivity in both tested cell lines. Based on the chemical structures of compounds 1–4, it is suggested that the presence of additional functional groups at the C‐15 position—a hydroxyl group in compound 2 and isomeric isoprene units in compounds 3 and 4—might be responsible for the reduction in the potential/selectivity. In silico studies show, for compounds 1–4, good predictions regarding bioavailability and ADME (absorption, distribution, metabolism, and excretion) properties as well as no alerts for PAINS (pan‐assay structures interference). In conclusion, ent‐kaurenoic acid (1), a common diterpenoid isolated in high amounts from different plants belonging to the Baccharis genus, has been shown to be a promising cytotoxic agent against an aggressive adenocarcinoma cell line (MDA‐MB‐23) and, if well exploited, could be used as a scaffold in the development of molecular prototypes for the treatment of breast cancer. Four natural diterpenes, ent‐kaurenoic acid (1) and its 15β‐hydroxy (2), 15β‐senecioyloxy (3), and 15β‐tiglinoyloxy (4) derivatives, isolated from Baccharis retusa and B. lateralis (Asteraceae), were assessed for their cytotoxic activity. Compound 1, with its promising cytotoxicity against the aggressive MDA‐MB‐23 cell line, may be used as a scaffold in the development of molecular prototypes for breast cancer treatment.