Cytotoxic and Apoptosis-Inducing Activities of Steviol and Isosteviol Derivatives against Human Cancer Cell Lines

• Published in: Chemistry & biodiversity Vol. 10; no. 2; pp. 177 - 188
• Main Authors: Ukiya, Motohiko, Sawada, Shingo, Kikuchi, Takashi, Kushi, Yasunori, Fukatsu, Makoto, Akihisa, Toshihiro
• Format: Journal Article
• Language: English
• Published: Zürich WILEY-VCH Verlag 01-02-2013; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis-inducing activity; Cell Line, Tumor; Cell Survival - drug effects; Cells; Cytotoxic activity; Cytotoxicity; Derivatives; Diterpenes, Kaurane - chemistry; Diterpenes, Kaurane - pharmacology; Humans; Isosteviol; Neoplasms - drug therapy; Proteins; Stevia - chemistry; Steviol
• ISSN: 1612-1872; 1612-1880
• DOI: 10.1002/cbdv.201200406

Seventeen steviol derivatives, i.e., 2–18, and 19 isosteviol derivatives, i.e., 19–37, were prepared from a diterpenoid glycoside, stevioside (1). Upon evaluation of the cytotoxic activities of these compounds against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK‐BR‐3) cancer cell lines, nine steviol derivatives, i.e., 5–9 and 11–14, and five isosteviol derivatives, i.e., 28–32, exhibited activities with single‐digit micromolar IC50 values against one or more cell lines. All of these active compounds possess C(19)‐O‐acyl group, and among which, ent‐kaur‐16‐ene‐13,19‐diol 19‐O‐4′,4′,4′‐trifluorocrotonate (14) exhibited potent cytotoxicities against four cell lines with IC50 values in the range of 1.2–4.1 μM. Compound 14 induced typical apoptotic cell death in HL60 cells upon evaluation of the apoptosis‐inducing activity by flow‐cytometric analysis. These results suggested that acylation of the 19‐OH group of kaurane‐ and beyerane‐type diterpenoids might be useful for enhancement of their cytotoxicities with apoptosis‐inducing activity.