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In this study, we investigated the antioxidant properties of triphenylphosphonium (TPP)-conjugated phenolic acids encapsulated in \u03b2-cyclodextrin (\u03b2-CD). We synthesized TPP conjugates of caffeic, coumaric, and cinnamic acids and formed inclusion complexes with \u03b2-CD. Our results showed successful encapsulation of TPP conjugates in \u03b2-CD with high efficiency. The TPP conjugates maintained antioxidant activity, with slight reductions observed in \u03b2-CD complexes. Furthermore, cell viability studies showed low cytotoxicity of the dds. Computational analyses revealed that TPP conjugation preserved the chemical reactivity of the phenolic acids. Molecular dynamics simulations demonstrated stable inclusion complexes with \u03b2-CD and the free energy calculations indicated that TPP conjugation significantly enhanced the ability of caffeic acid to translocate across mitochondrial membranes. These results highlight the potential of TPP-conjugated phenolic acids encapsulated in \u03b2-CD as effective antioxidants with improved mitochondrial targeting capabilities.<\/jats:p>","DOI":"10.3390\/antiox14040465","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T07:42:01Z","timestamp":1744616521000},"page":"465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Exploring the Mechanism of \u03b2-Cyclodextrin-Encased Phenolic Acids Functionalized with TPP for Antioxidant Activity and Targeting"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2300-9513","authenticated-orcid":false,"given":"Christopher","family":"Sbarbaro","sequence":"first","affiliation":[{"name":"Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andr\u00e9s Bello, Santiago 8370035, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeria","family":"M\u00e1rquez-Miranda","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andr\u00e9s Bello, Santiago 8370035, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7145-1920","authenticated-orcid":false,"given":"Mat\u00edas","family":"Leal","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica y Fisicoqu\u00edmica, Facultad de Ciencias Qu\u00edmicas y Farmac\u00e9uticas, Universidad de Chile, Santiago 8380494, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4756-1115","authenticated-orcid":false,"given":"Ricardo","family":"Pino-Rios","sequence":"additional","affiliation":[{"name":"Instituto de Ciencias Exactas y Naturales (ICEN), Universidad Arturo Prat, Playa Brava 3256, Iquique 1111346, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9945-7929","authenticated-orcid":false,"given":"Pedro","family":"Olivares","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andr\u00e9s Bello, Santiago 8370035, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makarena","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andr\u00e9s Bello, Santiago 8370035, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5394-322X","authenticated-orcid":false,"given":"Ignacio","family":"D\u00edaz-Franulic","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andr\u00e9s Bello, Santiago 8370035, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6857-3575","authenticated-orcid":false,"given":"Fernando","family":"Gonz\u00e1lez-Nilo","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andr\u00e9s Bello, Santiago 8370035, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8993-9353","authenticated-orcid":false,"given":"Osvaldo","family":"Y\u00e1\u00f1ez","sequence":"additional","affiliation":[{"name":"Centro de Modelaci\u00f3n Ambiental y Din\u00e1mica de Sistemas (CEMADIS), Universidad de las Am\u00e9ricas, Santiago 7500975, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yorley","family":"Duarte","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Integrative Biology, Facultad de Ciencias de la Vida, Universidad Andr\u00e9s Bello, Santiago 8370035, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Rudrapal, M., Khairnar, S.J., Khan, J., Bin Dukhyil, A., Ansari, M.A., Alomary, M.N., Alshabrmi, F.M., Palai, S., Deb, P.K., and Devi, R. 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