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Standard drugs currently used for the treatment of advanced CRC\u2014such as 5-fluorouracil (5FU)\u2014remain unsatisfactory in their results due to their high toxicity, high resistance, and adverse effects. In recent years, mitochondria have become an attractive target for cancer therapy due to higher transmembrane mitochondrial potential. We synthesized gallic acid derivatives linked to a ten-carbon aliphatic chain associated with triphenylphosphonium (TPP+C10), a lipophilic cationic molecule that induces the uncoupling of the electron transport chain (ETC). Other derivatives, such as gentisic acid (GA-TPP+C10), have the same effects on colorectal cancer cells. Although part of our group had previously reported preparing these structures by a convergent synthesis route, including their application via flow chemistry, there was no precedent for a new methodology for preparing these compounds. In this scenario, this study aims to develop a new linear synthesis strategy involving an essential step of Steglich esterification under mild conditions (open flask) and a high degree of reproducibility. Moreover, the study seeks to associate GA-TPP+C10 with 5FU to evaluate synergistic antineoplastic effects. In addition, we assess the antimigratory effect of GA-TPP+C10 and TPP+C10 using human and mouse metastatic CRC cell lines. The results show a new and efficient synthesis route of these compounds, having synergistic effects in combination with 5FU, increasing apoptosis and enhancing cytotoxic properties. Additionally, the results show a robust antimigratory effect of GATPP+C10 and TPP+C10, reducing the activation pathways linked to tumor progression and reducing the expression of VEGF and MMP-2 and MMP-9, common biomarkers of advanced CRC. Moreover, TPP+C10 and GA-TPP+C10 increase the activity of metabolic signaling pathways through AMPK activation. The data allow us to conclude that these compounds can be used for in vivo evaluations and are a promising alternative associated with conventional therapies for advanced colorectal cancer. Additionally, the reported intermediates of the new synthesis route could give rise to analog compounds with improved therapeutic activity.<\/jats:p>","DOI":"10.3390\/cancers16172980","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T09:26:51Z","timestamp":1724750811000},"page":"2980","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Antimigratory Effect of Lipophilic Cations Derived from Gallic and Gentisic Acid and Synergistic Effect with 5-Fluorouracil on Metastatic Colorectal Cancer Cells: A New Synthesis Route"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3993-6071","authenticated-orcid":false,"given":"Cristian","family":"Sua\u0301rez-Rozas","sequence":"first","affiliation":[{"name":"Centro de Qu\u00edmica M\u00e9dica, Instituto de Ciencias e Innovaci\u00f3n en Medicina, Facultad de Medicina, Cl\u00ednica Alemana Universidad del Desarrollo, Santiago 7610658, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3016-9133","authenticated-orcid":false,"given":"Jose\u0301 Antonio","family":"Jara","sequence":"additional","affiliation":[{"name":"Institute for Research in Dental Sciences (ICOD), Faculty of Dentistry, Universidad de Chile, Santiago 8330111, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gonzalo","family":"Cort\u00e9s","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Program, Biomedical Science Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8330111, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego","family":"Rojas","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Program, Biomedical Science Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8330111, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5025-9083","authenticated-orcid":false,"given":"Gabriel","family":"Araya-Valde\u0301s","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Program, Biomedical Science Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8330111, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfredo","family":"Molina-Berrios","sequence":"additional","affiliation":[{"name":"Institute for Research in Dental Sciences (ICOD), Faculty of Dentistry, Universidad de Chile, Santiago 8330111, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9558-0008","authenticated-orcid":false,"given":"Fabiola","family":"Gonza\u0301lez-Herrera","sequence":"additional","affiliation":[{"name":"Molecular and Clinical Program, Biomedical Science Institute (ICBM), Faculty of Medicine, Universidad de Chile, Santiago 8330111, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3944-3138","authenticated-orcid":false,"given":"Sebasti\u00e1n","family":"Fuentes-Retamal","sequence":"additional","affiliation":[{"name":"Escuela de Qu\u00edmica y Farmacia, Facultad de Medicina, Universidad Andr\u00e9s Bello, Santiago 8320000, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4379-2429","authenticated-orcid":false,"given":"Pablo","family":"Ar\u00e1nguiz-Urroz","sequence":"additional","affiliation":[{"name":"School of Health Science, Universidad de Vi\u00f1a del Mar, Vi\u00f1a del Mar 2580022, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2840-0666","authenticated-orcid":false,"given":"Paola Rossana","family":"Campod\u00f3nico","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica M\u00e9dica, Instituto de Ciencias e Innovaci\u00f3n en 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