{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T14:56:58Z","timestamp":1792076218194,"version":"4.4.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>\n                      In this study, a series of lipophilic and amphiphilic quinine derivatives were synthesized and structurally characterized, and the\n                      <jats:italic>in vitro<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results and discussion<\/jats:title>\n                    <jats:p>\n                      Among the 26 synthesized compounds, compound\n                      <jats:bold>22<\/jats:bold>\n                      exhibited the highest cytotoxic potency and selectivity toward CEM leukemia cells (CC\n                      <jats:sub>50<\/jats:sub>\n                      = 2.25 \u00b1 0.03 \u00b5M; SCI = 4.5). Mechanistic studies demonstrated that compound\n                      <jats:bold>22<\/jats:bold>\n                      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\n                      <jats:bold>22<\/jats:bold>\n                      , and PIM-1 kinase, supported by favorable MM\/GBSA binding free energy values.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Overall, these findings identify compound\n                      <jats:bold>22<\/jats:bold>\n                      as a promising PIM-1 kinase\u2013targeting antileukemic candidate.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1799674","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T04:21:48Z","timestamp":1776745308000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A novel quinine derivative as a PIM-1 kinase inhibitor induces apoptosis via mitochondrial depolarization with selective cytotoxicity in acute lymphoblastic leukemia cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Viviana","family":"Donoso-Bustamante","sequence":"first","affiliation":[{"name":"Laboratorio de S\u00edntesis y Reactividad de Compuestos Org\u00e1nicos, Departamento de Qu\u00edmica, Facultad de Ciencias Exactas, Universidad Andr\u00e9s Bello","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edison H.","family":"Osorio","sequence":"additional","affiliation":[{"name":"CBATA, Departamento de Ciencias B\u00e1sicas y \u00c1reas Comunes, Tecnol\u00f3gico de Antioquia Instituci\u00f3n Universitaria-TdeA","place":["Medell\u00edn, Colombia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela C.","family":"Torres","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso","place":["El Paso, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 A.","family":"L\u00f3pez-Saenz","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso","place":["El Paso, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato J.","family":"Aguilera","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso","place":["El Paso, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denisse A.","family":"Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso","place":["El Paso, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armando","family":"Varela-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Border Biomedical Research Center, The University of Texas at El Paso","place":["El Paso, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeray A.","family":"Rodr\u00edguez-N\u00fa\u00f1ez","sequence":"additional","affiliation":[{"name":"Laboratorio de S\u00edntesis y Reactividad de Compuestos Org\u00e1nicos, Departamento de Qu\u00edmica, Facultad de Ciencias Exactas, Universidad Andr\u00e9s Bello","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Echeverr\u00eda","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias del Ambiente, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile","place":["Santiago, Chile"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1002\/poc.1679","article-title":"Molecular dynamics simulation and MM\u2013PBSA calculations of sickle cell hemoglobin in dimer form with Val, Trp, or Phe at the lateral contact","volume":"23","author":"Abroshan","year":"2010","journal-title":"J. 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