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

Abstract

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 IC(50) 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 IC(50) 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.

Synthesis and Anticancer Evaluation of Complex Unsaturated Isosteviol-Derived Triazole Conjugates

“…Recent studies have revealed several potential mechanisms of action of isosteviol derivatives for anticancer activity [11,27]. From our gene microarray data from breast cancer patient tissues, MMP11 was found to be upregulated while HPSE2 was downregulated in breast cancer compared with normal control [28,29].…”

“…In particular, since the end of the 1990s, ent-beyrane diterpenoid isosteviol has attracted a great deal of attention from medicinal chemists as a native scaffold for organic chemistry and drug discovery [1][2][3]. With its unique rigid skeletal structure with six stereo centers, isosteviol derivatives have been shown to have numerous biological activities [4][5][6][7][8][9], particularly in the anticancer area [10][11][12][13][14][15].…”

Diterpenoids from Wedelia prostrata and Their Derivatives and Cytotoxic Activities

“…SW480 cells were incubated with the test compound (0, 0.25, 0.50 and 1.00 mg/l, respectively) for 24 h, and then the cells were analyzed by means of flow cytometry (Fig. [23] [24] In normal cells, PS is predominantly present on cytosolic side of the membrane, while it gets translocated towards outer side of the membrane when cells undergo apoptosis. Apoptotic cells can be detected by virtue of binding of annexin V-FITC to phosphotidyl serine (PS) present on the outer side of the cell membrane.…”

Inhibitory Effect of Steviol and Its Derivatives on Cell Migration via Regulation of Tight Junction-related Protein Claudin 8

“…또한, 스테비올과 그 유도체인 스테비 오사이드, 리바우디오사이드는 인체 유해성에 대해 보 고되지 않았고 피부 섬유아세포 콜라젠 합성을 통해 피부 탄력 향상 및 주름 개선 효과가 보고되어 있다 [3]. 특히 스테비올에 여러 개의 당이 결합된 스테비오사이 드는 고농도 조건에서도 별다른 독성이 나타나지 않는 것으로 알려져 안전성이 입증되었고 인간 암세포에 대 해 세포사멸(apoptosis)을 유발한다고 알려져 있다 [4,5].…”