Cytotoxicity, Molecular Docking, ADMET and DFT Analysis of Alkaloids from Roots and Fruits of Vepris dainelli

Background: Vepris dainelli (Rutaceae) is an endemic medicinal plant to Ethiopia, traditionally used for the treatment of abdominal cramp, intestinal worms, skin diseases and tooth pain. Methods: Roots and fruit extracts were subjected to silica gel column chromatographic separation to afford five alkaloids, reported for the first time from the species. The cytotoxic effects of alkaloids (2-4) were evaluated in vitro against the estrogen-responsive MCF-7 and estrogen-unresponsive MDA-MB-231 human breast cancer cell lines by MTS assay. Result: The results revealed that alkaloids (2-4) induced a significant reduction in cell growth of both breast cancer cell lines in a dose-dependent manner. Evodiamine (4) showed the highest potency against the aggressive metastatic MDA-MB-231 cell line at low micromolar concentrations. In addition, it highly arrested the cells in the G2/M phase, especially the MCF-7 cell line. By contrast, evoxanthine (2) and arborinine (3) exhibited higher cytotoxicity against MCF-7 than MDA-MB-231, and showed influencing the cell cycle in both cell lines by arresting some cells in the G2/M phase, preventing cells with damaged DNA from entering mitosis. Molecular docking analysis showed that all alkaloids inhibit human topoisomerase II α, compared with vosaroxin anti-cancer agent under clinical trial. The ADMET studies showed the alkaloids' highest drug-likeness properties, suggesting these alkaloids act as a drug and exhibit remarkable biological activities, except (5). DFT calculations indicated that studied alkaloids showed the lowest gap energy and were chemically reactive. Conclusion: We found that the results obtained from molecular docking, drug-likeness properties, ADMET analysis and DFT calculation are in good agreement with experimental studies. Hence, evoxanthine (2), arborinine (3), and evodiamine (4) may serve as a lead molecule that could be developed into potent topoisomerase II α inhibitors against human breast cancer cells.