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Background Acute lymphoblastic leukemia (ALL) remains a major therapeutic challenge, particularly in adult patients with poor tolerance to intensive chemotherapy, underscoring the need for novel and selective antileukemic agents that target more specific pharmacological targets and contribute to the development of new, less invasive therapeutic interventions. Quinine, a natural alkaloid, and its derivatives have demonstrated promising anticancer properties that could contribute to this development. Purpose In this study, a series of lipophilic and amphiphilic quinine derivatives were synthesized and structurally characterized, and the in vitro cytotoxicity was evaluated against CEM and Jurkat leukemia cell lines and non-cancerous fibroblasts (Hs-27). To elucidate the mechanism of action, analyses revealed a strong affinity of the compounds for PIM-1 kinase, a protein overexpressed in most cases of ALL. Results and discussion Among the 26 synthesized compounds, compound 22 exhibited the highest cytotoxic potency and selectivity toward CEM leukemia cells (CC 50 = 2.25 ± 0.03 µM; SCI = 4.5). Mechanistic studies demonstrated that compound 22 induces apoptosis by externalizing phosphatidylserine, depolarizing the mitochondrial membrane, activating caspase-3/7, and causing DNA fragmentation, without causing cell-cycle arrest. Molecular docking and molecular dynamics simulations revealed strong, stable interactions between the most active compounds, particularly compound 22 , and PIM-1 kinase, supported by favorable MM/GBSA binding free energy values. Conclusion Overall, these findings identify compound 22 as a promising PIM-1 kinase–targeting antileukemic candidate.
Donoso-Bustamante et al. (Tue,) studied this question.