Bio-Guided Fractionation of Ethanol Extract of Leaves of Kunt (Rutaceae) Led to the Isolation of Two Cytotoxic Quinoline Alkaloids: Evidence of Selectivity Against Leukemia Cells

Bio-guided fractionation performed on the leaves-derived ethanol extract of (Rutaceae), a plant used in traditional medicine, led to the isolation of two alkaloids, kokusaginine and flindersiamine , as main cytotoxic agents. Primary ethanolic extract and raw fractions exhibited cell inhibition against five cancer cell lines at different levels (25-97% inhibition at 50 µg/mL) as well as isolated alkaloids - (30-90% inhibition at 20 µM). Although alkaloid generally was the most active compound, both alkaloids showed a selective effect on K562, a human chronic myelogenous leukemia cell line. The E1-like ubiquitin-activating enzymes (e.g., UBA5) have been recently described as important targets for future treatment of cancer progression, such as leukemia, among others. Therefore, as a rationale to the observed cytotoxic selectivity, an in-silico evaluation by molecular docking and molecular dynamics was also explored. Compounds - exhibited good performance on the interaction within the active site of UBA5.