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Consequently, the development of potent, low\u2010toxicity P\u2010gp inhibitors represents a crucial direction in anticancer drug research. Based on our group's prior work on P\u2010gp inhibitors and supported by molecular docking analysis, 21 novel tetrahydroisoquinoline derivatives were designed and synthesized in this study. Their ability to reverse MDR was assessed in the human esophageal carcinoma multidrug\u2010resistant cell line Eca109\/VCR. The most active compound\n                    <jats:bold>21<\/jats:bold>\n                    demonstrated a superior reversal fold (RF\u2009=\u2009654) compared to the third\u2010generation P\u2010gp inhibitor\n                    <jats:bold>TQ<\/jats:bold>\n                    , as confirmed by colony formation and flow cytometry assays. Mechanistic investigations, including chemosensitization, intracellular fluorescent substrate accumulation, and molecular docking studies, verified that the MDR reversal effect of compound\n                    <jats:bold>21<\/jats:bold>\n                    is mediated through P\u2010gp inhibition. This work provides a new strategic direction for developing tetrahydroisoquinoline\u2010based sensitizers to overcome tumor drug resistance.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202501112","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T14:52:08Z","timestamp":1777560728000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery and Evaluation of 6,7\u2010Dimethoxy\u20101,2,3,4\u2010Tetrahydroisoquinoline Derivatives as P\u2010gp Inhibitors to Overcome Multidrug Resistance in Eca109\/VCR Cells"],"prefix":"10.1002","volume":"21","author":[{"given":"Wen\u2010Jing","family":"Lai","sequence":"first","affiliation":[{"name":"College of Chemistry and Environmental Engineering Sichuan University of Science and Engineering  Zigong China"},{"name":"Department of Medicinal Chemistry Third Military Medical University  Chongqing 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