{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:32:17Z","timestamp":1787567537625,"version":"build-2736575974"},"reference-count":59,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T00:00:00Z","timestamp":1787443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituci\u00f3n Universitaria ITM, Colombia","award":["P23203"],"award-info":[{"award-number":["P23203"]}]},{"name":"Universidad de Antioquia UdeA, Colombia"},{"id":[{"id":"https:\/\/ror.org\/03bp5hc83","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Universidad Nacional de La Plata UNLP, Argentina"},{"id":[{"id":"https:\/\/ror.org\/01tjs6929","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Chlorogenic acid (CGA) exhibits anticancer activity in colorectal cancer (CRC), but its clinical application is limited by low lipophilicity. To improve its physicochemical properties, four CGA esters (methyl, ethyl, n-propyl, and n-butyl chlorogenates) were synthesized and evaluated. Physicochemical properties were characterized in silico, and their biological activity was assessed in SW480, HT-29, and non-tumoral NCM460 cell lines using viability assays and flow cytometry. Molecular docking studies were performed to investigate the interactions of CGA and its esters with proteins involved in cell-proliferation-related signaling pathways. In silico analysis showed a progressive increase in LogP values across ester derivatives. All esters complied with Lipinski\u2019s rule of five, whereas none met Veber\u2019s rule due to their predicted topological polar surface area (TPSA) values. The esters induced dose- and time-dependent reductions in cell viability, with n-butyl chlorogenate exhibiting the strongest cytotoxic activity and a significantly lower IC50 value within the tested concentration range. This derivative showed preferential cytotoxic activity toward SW480 cells while exhibiting only limited effects in non-tumoral NCM460 cells. In addition, n-butyl chlorogenate induced changes in mitochondrial oxidative status and phosphatidylserine externalization, consistent with apoptosis-associated cellular changes. Overall, these findings demonstrate that esterification modifies the physicochemical profile of CGA ester derivatives and is associated with enhanced cytotoxic activity. Increased lipophilicity was associated with enhanced cytotoxic activity, supporting further optimization of these compounds for CRC research.<\/jats:p>","DOI":"10.3390\/molecules31172952","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:20:02Z","timestamp":1787563202000},"page":"2952","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Improved Lipophilicity Is Associated with the Cytotoxic Activity of Chlorogenic Acid Esters in In Vitro Colorectal Cancer Models"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7082-211X","authenticated-orcid":false,"given":"Ana Mar\u00eda","family":"Casta\u00f1eda-Cifuentes","sequence":"first","affiliation":[{"name":"de Investigaci\u00f3n e Innovaci\u00f3n Biom\u00e9dica GI<sup>2<\/sup>B, Facultad de Ciencias Exactas y Aplicadas, Instituci\u00f3n Universitaria ITM, Medell\u00edn 050012, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9784-874X","authenticated-orcid":false,"given":"Johanna","family":"Pedroza-D\u00edaz","sequence":"additional","affiliation":[{"name":"de Investigaci\u00f3n e Innovaci\u00f3n Biom\u00e9dica GI<sup>2<\/sup>B, Facultad de Ciencias Exactas y Aplicadas, Instituci\u00f3n Universitaria ITM, Medell\u00edn 050012, Colombia"},{"name":"Grupo de Investigaci\u00f3n en Biolog\u00eda M\u00e9dica (BioMed), Facultad de Ciencias Exactas y Aplicadas, Instituci\u00f3n Universitaria ITM, Medell\u00edn 050012, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0514-5957","authenticated-orcid":false,"given":"Gloria A.","family":"Santa-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"de Investigaci\u00f3n e Innovaci\u00f3n Biom\u00e9dica GI<sup>2<\/sup>B, Facultad de Ciencias Exactas y Aplicadas, Instituci\u00f3n Universitaria ITM, Medell\u00edn 050012, Colombia"},{"name":"Grupo de Investigaci\u00f3n en Biolog\u00eda M\u00e9dica (BioMed), Facultad de Ciencias Exactas y Aplicadas, Instituci\u00f3n Universitaria ITM, Medell\u00edn 050012, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1893-2191","authenticated-orcid":false,"given":"Isabel Cristina","family":"Henao-Casta\u00f1eda","sequence":"additional","affiliation":[{"name":"Grupo de Investigaci\u00f3n en Sustancias Bioactivas, Facultad de Ciencias Farmac\u00e9uticas y Alimentarias, Universidad de Antioquia, Medell\u00edn 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea Johanna Andrea","family":"B\u00e1ez","sequence":"additional","affiliation":[{"name":"Grupo de Investigaci\u00f3n en Sustancias Bioactivas, Facultad de Ciencias Farmac\u00e9uticas y Alimentarias, Universidad de Antioquia, Medell\u00edn 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7812-0043","authenticated-orcid":false,"given":"Jorge L.","family":"Jios","sequence":"additional","affiliation":[{"name":"Laboratorio UPL (UNLP-CIC), Camino Centenario e\/505 y 508 (1897) M.B. Gonnet, Departamento de Qu\u00edmica, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Rep\u00fablica Argentina, 47 esq. 115, La Plata 1900, Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Laura","family":"Di Virgilio","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Inorg\u00e1nica (CEQUINOR, CONICET), Facultad de Ciencias Exactas, Universidad Nacional de la Plata Facultad, 47 Y 115, La Plata 1900, Buenos Aires, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,23]]},"reference":[{"key":"ref_1","unstructured":"(2025, August 23). International Agency for Research on Cancer and IARC Cancer Today. Available online: https:\/\/gco.iarc.fr\/today\/en."},{"key":"ref_2","unstructured":"International Agency for Research on Cancer (2024, September 20). IARC Global Cancer Observatory: Cancer Tomorrow. 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