ABSTRACT
Cardiac glycosides, such as digoxin and digitoxin, are compounds that interact with Na+ /K+ -ATPase to induce anti-neoplastic effects; however, these cardiac glycosides have narrow therapeutic index. Thus, semi-synthetic analogs of digitoxin with modifications in the sugar moiety has been shown to be an interesting approach to obtain more selective and more effective analogs than the parent natural product. Therefore, the aim of this study was to assess the cytotoxic potential of novel digitoxigenin derivatives, digitoxigenin-α-L-rhamno-pyranoside (1) and digitoxigenin-α-L-amiceto-pyranoside (2), in cervical carcinoma cells (HeLa) and human diploid lung fibroblasts (Wi-26-VA4). In addition, we studied the anticancer mechanisms of action of these compounds by comparing its cytotoxic effects with the potential to modulate the activity of three P-type ATPases; Na+ /K+ -ATPase, sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA), and plasma membrane Ca2+ -ATPase (PMCA). Briefly, the results showed that compounds 1 and 2 were more cytotoxic and selectivity for HeLa tumor cells than the nontumor cells Wi-26-VA4. While the anticancer cytotoxicity in HeLa cells involves the modulation of Na+ /K+ -ATPase, PMCA and SERCA, the modulation of these P-type ATPases was completely absent in Wi-26-VA4 cells, which suggest the importance of their role in the cytotoxic effect of compounds 1 and 2 in HeLa cells. Furthermore, the compound 2 inhibited directly erythrocyte ghosts PMCA and both compounds were more cytotoxic than digitoxin in HeLa cells. These results provide a better understanding of the mode of action of the synthetic cardiac glycosides and highlights 1 and 2 as potential anticancer agents.
Subject(s)
Cell Membrane/enzymology , Digitoxigenin , Plasma Membrane Calcium-Transporting ATPases/metabolism , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Cell Membrane/genetics , Digitoxigenin/analogs & derivatives , Digitoxigenin/pharmacology , HeLa Cells , Humans , Plasma Membrane Calcium-Transporting ATPases/genetics , Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics , Sodium-Potassium-Exchanging ATPase/geneticsABSTRACT
Correction for 'The asymmetric syntheses of cryptocaryols A and B' by Alhanouf Zakaria Aljahdali et al., Chem. Commun., 2018, 54, 3428-3435.
ABSTRACT
The recent total syntheses of cryptocaryols A and B are reviewed. These efforts include the correction of the initially assigned absolute and relative stereochemistry of this class of natural products. In addition to enabling the initial structure activity relationships for this class of natural products, these syntheses demonstrated the practical utility of several novel synthetic approaches.
