{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T13:10:07Z","timestamp":1785244207467,"version":"3.55.0"},"reference-count":41,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Smart Molecules"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Small molecule blockade of the programmed death receptor 1 (PD\u20101)\/programmed cell death ligand 1 (PD\u2010L1) pathway represents a promising approach for tumor immunotherapy. Based on the previously developed 3D\u2010quantitative structure\u2010activity\u00a0relationship pharmacophore model for PD\u2010L1 inhibitors, virtual screening followed by homogeneous time\u2010resolved fluorescence (HTRF) activity testing identified the compound {1\u2010[(biphenyl\u20104\u2010yl)methyl]\u20107\u2010methoxy\u20101,2,3,4\u2010tetrahydroisoquinolin\u20106\u2010yl}acetic acid methyl ester (Compound\n                    <jats:bold>Y6<\/jats:bold>\n                    ) as a hit. Analysis of computational docking results of compound\n                    <jats:bold>Y6<\/jats:bold>\n                    with PD\u2010L1 suggested targeting the methyl acetate substituent at position 6 for optimization. Guided by this, 20 new derivatives were designed and synthesized. The synthesized compounds were subjected to HTRF test and 6 compounds with significant protein blocking effects were screened for subsequent surface plasmon resonance (SPR) test. Subsequent SPR analysis confirmed strong binding of these 6 compounds to hPD\u2010L1 protein with\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>D<\/jats:sub>\n                    \u00a0values ranging from 0.24 to 21.31\u00a0\u03bcM. Several derivatives displayed improved or\u00a0comparable PD\u2010L1 binding affinity relative to the lead compound\n                    <jats:bold>Y6<\/jats:bold>\n                    (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>D<\/jats:sub>\n                    \u00a0=\u00a011.3\u00a0\u03bcM). A co\u2010incubation system (PD\u20101\n                    <jats:sup>+<\/jats:sup>\n                    Jurkat T\/PD\u2010L1\n                    <jats:sup>+<\/jats:sup>\n                    HepG2) was established to evaluate functional immune restoration. This evaluation revealed that compound\n                    <jats:bold>Y7f<\/jats:bold>\n                    effectively promoted HepG2 cells death by restoring T cell immune function. MD simulations identify\n                    <jats:bold>(1R,16R)\u2010Y7f<\/jats:bold>\n                    as the most potent PD\u2010L1 dimerization inducer within the compound\n                    <jats:bold>Y7f<\/jats:bold>\n                    stereoisomer series. The results indicated that the biphenyl\u2010tetrahydroisoquinoline scaffold is a promising structural framework\u00a0for developing novel PD\u20101\/PD\u2010L1 inhibitors and deserves further investigation.\n                  <\/jats:p>","DOI":"10.1002\/smo2.70075","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T12:44:26Z","timestamp":1785242666000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, synthesis and activity evaluation of tetrahydroisoquinoline\u2010based programmed cell death ligand 1 inhibitors"],"prefix":"10.1002","author":[{"given":"Menglin","family":"Yu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Fine Chemicals Department of Pharmaceutical Engineering School of Chemical Engineering Dalian University of Technology  Dalian Liaoning 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