Semi-Synthetic Derivatives from a Lupane-Type Triterpene Isolated from <i>Phoradendron wattii</i> with Anti-Leukemia Activity

Introduction: Leukemia is among the most common types of cancer. Currently, the main anti-leukemia treatments have significant drawbacks, which has led to the search for new and better drugs, especially those developed from natural products. Objective: The aim of this work was to perform simple modifications to a lupane-type pentacyclic triterpene isolated from Phoradendron wattii , in order to generate new semi-synthetic analogues for their possible effect against a panel of leukemia cell lines. Methods: Simple structural modifications on the triterpene 3 α ,23- O -isopropylidenyl-3 α ,23-dihydroxylup-20(29)-en-28-oic acid ( T2 ) isolated from Phoradendron wattii were performed and evaluated against a panel of leukemia cell lines and normal mononuclear cells (MNC). In addition, molecular docking analysis was used to better understand the possible mechanism of action, employing key molecular targets used in the search for compounds with anti-leukemic activity (BCL-2 and EGFR). Results: Of the all derivatives synthetized ( T2a - T2f ), the compound ( T2e ), 3 α ,23-dihydroxy-30-oxolup-20(29)-en-28-ol, showed inhibition in leukemia cell lines (CCRF-CEM, REH, JURKAT, MOLT-4, and THP-1) and induction of death by apoptosis to different degrees. Moreover, it showed a minor cytotoxic effect on MNC and was found to interact with BCL-2 and EGFR in silico . Conclusion: The present work shows that simple modifications at promising sites in the lupane-type pentacyclic triterpene can generate derivatives with enhanced biological activity against leukemia cell lines. The T2e derivative is a promising candidate for future research.