Phenanthrene Alkaloids From <i>Guatteria Olivacea</i> as Topoisomerase II Inhibitors: Theoretical Insights and Cytotoxic Evaluation

ABSTRACT Phenanthrene alkaloids are rare natural products structurally related to aporphine analogues and display diverse biological activities. Three phenanthrene alkaloids isolated from Guatteria olivacea —atherosperminine (A1), argentinine (A2), and atherosperminine N‐oxide (A3)—were investigated using DFT calculations to characterize their structural, electronic, and reactivity features, as well as solvation behavior. Molecular docking with DNA‐topoisomerase II complex indicated favorable interactions, with binding energies of −8.3, −8.2, and −8.5 kcal mol −1 for A1, A2, and A3, respectively. Docking studies with human serum albumin (HSA), a key protein involved in drug transport, suggested preferential binding to Drug Site 1. In vitro cytotoxicity assays revealed that A1 exhibited measurable activity against MCF‐7, HCT116, HepG2, and HL‐60 cells, with IC 50 values of 12.70, 10.22, 13.01, and 10.44 µg mL − 1 , respectively. A2 showed limited cytotoxicity, with detectable activity only in HCT116 cells (IC 50 = 20.36 µg mL − 1 ), whereas A3 remained inactive under the tested conditions (IC 50 &gt; 25 µg mL − 1 ). Molecular dynamics simulations over 100 ns demonstrated that all three alkaloids remained stably bound within the drug‐binding pocket of the DNA–topoisomerase II cleavage complex, contributing to complex stabilization. ADME predictions highlighted A1 as having the most favorable balance between lipophilicity and solubility. Overall, atherosperminine emerged as the most promising bioactive alkaloid.