The Finally Rewarding Search for A Cytotoxic Isosteviol Derivative

Abstract

Acid hydrolysis of stevioside resulted in a 63% yield of isosteviol (1), which served as a starting material for the preparation of numerous amides. These compounds were tested for cytotoxic activity, employing a panel of human tumor cell lines, and almost all amides were found to be non-cytotoxic. Only the combination of isosteviol, a (homo)-piperazinyl spacer and rhodamine B or rhodamine 101 unit proved to be particularly suitable. These spacered rhodamine conjugates exhibited cytotoxic activity in the sub-micromolar concentration range. In this regard, the homopiperazinyl-spacered derivatives were found to be better than those compounds with piperazinyl spacers, and rhodamine 101 conjugates were more cytotoxic than rhodamine B hybrids.

F16 Hybrids Derived from Steviol or Isosteviol Are Accumulated in the Mitochondria of Tumor Cells and Overcome Drug Resistance

“…The obtained spectroscopic data agreed perfectly with the expected values. The assignment of the signals of the (iso)-steviol skeleton in the respective NMR spectra followed the assignments previously made [ 15 ].…”

“…3368br, 2923m, 2850m, 1725s, 1629w, 1604s, 1562m, 1496m, 1446br, 1433m, 1375w, 1318w, 1280w, 1244m, 1209w, 1166w, 1146w, 1131m, 1112w, 1095w, 1056m, 1040w, 966w, 928w, 818w, 745m, 665w, 570w, 508w, 423w cm −1 ; UV-Vis (MeOH): λ max (log ε) = 434.17 nm (4.02); 1 H NMR (500 MHz, DMSO-d 6 ): δ =12.14 (s, 1H, NH), 8.83 (d, J = 5. 5 Hz,1H,8.61 (d,J = 7.9 Hz,1H,8.41 (t,J = 7.6 Hz,1H,8.35 (d,J = 15.6 Hz,1H,8.32 (s,1H,, 8.12 (d, J = 7.2 Hz, 1H, 32-H), 7.76 (t, J = 6.8 Hz, 1H, 24-H), 7.52 (d, J = 7.0 Hz, 1H, 35-H), 7.38 (d,J = 15.7 Hz,1H,2H,2H,1H,1H,2.20 (dd,J = 18.4,3.6 Hz,1H,15 -16), 176.8 (C-18), 154.4 (C-27), 145.5 (C-23), 145.4 (C-37), 144.0 (C-25), 139.2 (C-29), 137.7 (C-36), 125.7 (C-31), 124.4 (C-26), 123.4 (C-34), 123.2 (C-24), 121.8 (C-33), 120.4 (C-32), 119.6, 113.9 (C-30), 113.1 (C-35), 110.1 (C-28), 62.2 (C-21), 56.4 (C-22), 56.1 (C-5), 54.1 (C-9), 53.6 (C-14), 48.3 (C-13), 48.2 (C-15), 43.6 (C-4), 40.7 (C-7), 39.4 (C-1), 39.3 (C-8), 37.8 (C-10), 37.7 (C-3), 37.0 (C-12), 28.4 (C-19), 21.7 (C-6), 20.2 (C-17), 18.9 (C-11), 18.8 (C-2), 13.0 (C-20) ppm; MS (ESI, MeOH/DMSO, 4:1): m/z (%) 566 (65%, [M − Br] + ; analysis calcd. for C 37 H 45 N 2 O 3 Br (645.67): C 68.83,H 7.02,N 4.34;found: C 68.60,H 7.19, Following GPB from 1 (0.5 g, 1.57 mmol), K 2 CO 3 (0.434 g, 3.1 mmol) and 1,3dibromopropane (0.64 mL, 6.3 mmol) followed by chromatography (SiO 2 , hexanes/ethyl acetate, 6:1), 14 (0.3 g, 44%) was obtained as a colorless solid: R f = 0.…”

“…In extensions of our previous investigations of triterpenes to diterpenes [ 12 , 13 , 14 ], we were able to present and investigate cytotoxic derivatives of isosteviol, a stachane-type diterpene, for the first time and to achieve initial success [ 15 ]. Therefore, it was obvious to also make corresponding F16 derivatives of steviol and isosteviol synthetically accessible and to investigate their cytotoxic potential.…”