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Among malignant tumor types, squamous cell carcinoma-esophageal cancer (EC) is usually located in the mouth, with approximately 90% located mainly on the tongue and floor of the mouth. Piplartine is an alkamide found in certain species of the genus Piper and presents many pharmacological properties including antitumor activity. In the present study, the cytotoxic potential of a collection of piplartine analogs against human oral SCC9 carcinoma cells was evaluated. The analogs were prepared via Fischer esterification reactions, alkyl and aryl halide esterification, and a coupling reaction with PyBOP using the natural compound 3,4,5-trimethoxybenzoic acid as a starting material. The products were structurally characterized using 1H and 13C nuclear magnetic resonance, infrared spectroscopy, and high-resolution mass spectrometry for the unpublished compounds. The compound 4-methoxy-benzyl 3,4,5-trimethoxybenzoate (9) presented an IC50 of 46.21 \u00b5M, high selectively (SI &gt; 16), and caused apoptosis in SCC9 cancer cells. The molecular modeling study suggested a multi-target mechanism of action for the antitumor activity of compound 9 with CRM1 as the main target receptor.<\/jats:p>","DOI":"10.3390\/molecules28041675","type":"journal-article","created":{"date-parts":[[2023,2,10]],"date-time":"2023-02-10T01:35:29Z","timestamp":1675992929000},"page":"1675","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Molecular Modeling and In Vitro Evaluation of Piplartine Analogs against Oral Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"28","author":[{"given":"Rayanne H. N.","family":"Silva","sequence":"first","affiliation":[{"name":"Laboratory of Pharmaceutical Chemistry, Department of Pharmaceutical Sciences, Federal University of Para\u00edba, Cidade Universit\u00e1ria, Jo\u00e3o Pessoa 58051-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tha\u00edssa Q.","family":"Machado","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Applied Science for Health Products, Faculty of Pharmacy, Fluminense Federal University, Niteroi 24241-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8366-3146","authenticated-orcid":false,"given":"Anna Carolina C.","family":"da Fonseca","sequence":"additional","affiliation":[{"name":"Postgraduate Program in Dentistry, Health Institute of Nova Friburgo, Fluminense Federal University, Nova Friburgo 28625-650, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Tejera","sequence":"additional","affiliation":[{"name":"Bio-Cheminformatics Research Group, Universidad de Las Am\u00e9ricas, Quito 170516, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3710-0035","authenticated-orcid":false,"given":"Yunierkis","family":"Perez-Castillo","sequence":"additional","affiliation":[{"name":"Facultad de Ingenier\u00eda y Ciencias Aplicadas, \u00c1rea de Ciencias Aplicadas, Universidad de Las Am\u00e9ricas, Quito 170516, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3972-5530","authenticated-orcid":false,"given":"Bruno K.","family":"Robbs","sequence":"additional","affiliation":[{"name":"Departamento de Ci\u00eancia B\u00e1sica, Instituto de Sa\u00fade de Nova Friburgo, Universidade Federal Fluminense, Nova Friburgo 28625-650, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7180-4896","authenticated-orcid":false,"given":"Dami\u00e3o P.","family":"de Sousa","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Chemistry, Department of Pharmaceutical Sciences, Federal University of Para\u00edba, Cidade Universit\u00e1ria, Jo\u00e3o Pessoa 58051-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,9]]},"reference":[{"key":"ref_1","unstructured":"(2018, July 09). 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