{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T23:59:18Z","timestamp":1766707158569,"version":"3.48.0"},"reference-count":72,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T00:00:00Z","timestamp":1766620800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273794"],"award-info":[{"award-number":["82273794"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22473062"],"award-info":[{"award-number":["22473062"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22293030"],"award-info":[{"award-number":["22293030"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22293032"],"award-info":[{"award-number":["22293032"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82073879"],"award-info":[{"award-number":["82073879"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006606","name":"Natural Science Foundation of Tianjin","doi-asserted-by":"publisher","award":["23JCQNJC01420"],"award-info":[{"award-number":["23JCQNJC01420"]}],"id":[{"id":"10.13039\/501100006606","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006606","name":"Natural Science Foundation of Tianjin","doi-asserted-by":"publisher","award":["23JCZDJC00260"],"award-info":[{"award-number":["23JCZDJC00260"]}],"id":[{"id":"10.13039\/501100006606","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Haihe Laboratory of Sustainable Chemical Transformations","award":["25HHWCSS00004"],"award-info":[{"award-number":["25HHWCSS00004"]}]},{"name":"Guangzhou Laboratory","award":["GZNL2023A01002"],"award-info":[{"award-number":["GZNL2023A01002"]}]},{"name":"Scientific Instrument and Technology R&D Project of Nankai University","award":["24NKSYJS09"],"award-info":[{"award-number":["24NKSYJS09"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Macrocyclic drugs are promising for targeting undruggable proteins, including those in cancer. Our prior work identified BE-43547A2 (BE) as a selective inhibitor of pancreatic cancer stem cells in PANC-1 cultures, but its high lipophilicity limits clinical application. To address this, we designed derivatives retaining BE\u2019s backbone while modifying tail groups to improve its properties. A concise total synthesis enabled a versatile late-stage intermediate (compound 17), serving as a platform for efficient diversification of BE analogs via modular click chemistry. This approach introduced a central triazole ring connected by flexible alkyl spacers. Key properties, including lipophilicity, solubility, and Caco-2 permeability, were experimentally determined. These derivatives exhibited reduced lipophilicity and improved solubility but unexpectedly lost cellular activity. Direct target engagement studies using MicroScale Thermophoresis (MST) revealed compound-dependent deactivation mechanisms: certain derivatives retained binding to eEF1A1 with only modestly reduced affinity (e.g., compound 29), while others showed no detectable binding (e.g., compound 31). Microsecond-scale molecular dynamics simulations and free-energy calculations showed that, for derivatives retaining target affinity, tail modifications disrupted the delicate balance of drug\u2013membrane and drug\u2013solvent interactions, resulting in substantially higher transmembrane free-energy penalties (&gt;5 kcal\/mol) compared to active compounds (&lt;2 kcal\/mol). These insights emphasize the need to simultaneously preserve both target engagement and optimal permeability when modifying side chains in cell-permeable macrocyclic peptides, positioning compound 17 as a robust scaffold for future lead optimization. This work furnishes a blueprint for balancing drug-like properties with therapeutic potency in macrocyclic therapeutics.<\/jats:p>","DOI":"10.3390\/md24010013","type":"journal-article","created":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T23:52:27Z","timestamp":1766706747000},"page":"13","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fine-Tuning Side Chain Substitutions: Impacts on the Lipophilicity\u2013Solubility\u2013Permeability Interplay in Macrocyclic Peptides"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3664-0427","authenticated-orcid":false,"given":"Yangping","family":"Deng","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hengwei","family":"Bian","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, China"},{"name":"Haihe Laboratory of Sustainable Chemical Transformations, 6 Keyanxi Road, Tianjin 300192, China"},{"name":"Research Center for Analytical Sciences, Tianjin Key Laboratory of Biosensing and Molecular Recognition, College of Chemistry, Nankai University, Tianjin 300071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongbo","family":"Li","sequence":"additional","affiliation":[{"name":"Accendatech Company, Ltd., Tianjin 300193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingjun","family":"Cui","sequence":"additional","affiliation":[{"name":"Accendatech Company, Ltd., Tianjin 300193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sizheng","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8820-1496","authenticated-orcid":false,"given":"Li","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, China"},{"name":"Haihe Laboratory of Sustainable Chemical Transformations, 6 Keyanxi Road, Tianjin 300192, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuemei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Accendatech Company, Ltd., Tianjin 300193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuo","family":"Shen","sequence":"additional","affiliation":[{"name":"Accendatech Company, Ltd., Tianjin 300193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fengyue","family":"Li","sequence":"additional","affiliation":[{"name":"Accendatech Company, Ltd., Tianjin 300193, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1317-7097","authenticated-orcid":false,"given":"Yue","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, China"},{"name":"Haihe Laboratory of Sustainable Chemical Transformations, 6 Keyanxi Road, Tianjin 300192, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0908-0046","authenticated-orcid":false,"given":"Haohao","family":"Fu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, China"},{"name":"Haihe Laboratory of Sustainable Chemical Transformations, 6 Keyanxi Road, Tianjin 300192, China"},{"name":"Research Center for Analytical Sciences, Tianjin Key Laboratory of Biosensing and Molecular Recognition, College of Chemistry, Nankai University, Tianjin 300071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,25]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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