{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T22:51:17Z","timestamp":1787784677353,"version":"build-2784847793"},"reference-count":47,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:00:00Z","timestamp":1781308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["PID2021-127471OB-I00"],"award-info":[{"award-number":["PID2021-127471OB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"award":["PID2021-127471OB-I00"],"award-info":[{"award-number":["PID2021-127471OB-I00"]}],"id":[{"id":"https:\/\/ror.org\/05r0vyz12","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008431","name":"Consejer\u00eda de Educaci\u00f3n de la Junta de Castilla y Le\u00f3n","doi-asserted-by":"publisher","award":["SA021G24"],"award-info":[{"award-number":["SA021G24"]}],"id":[{"id":"10.13039\/501100008431","id-type":"DOI","asserted-by":"publisher"}]},{"award":["SA021G24"],"award-info":[{"award-number":["SA021G24"]}],"id":[{"id":"https:\/\/ror.org\/00t864161","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Microtubule-targeting agents represent a pillar of cancer chemotherapy; however, their clinical utility is constrained by significant toxicity, pharmacokinetic instability, and susceptibility to multidrug resistance transporters. This study aimed to explore the impact of replacing substituted phenyl rings with a naphthalene moiety in sulfonamide-based colchicine-site ligands, with the goal of identifying new antiproliferative candidates with improved profiles. Methods: We designed, synthesized, and evaluated a library of 35 naphthalene sulfonamides bearing varied aryl groups and sulfonamide nitrogen substituents. We assessed the antiproliferative activity against multiple cancer cell lines. Mechanistic studies, including fluorescence microscopy, cell cycle analysis, and cell death assays, were performed to evaluate the effect of these compounds on microtubule polymerization dynamics and cell fate. Molecular docking and in silico pharmacokinetic profiling were carried out to support the proposed binding mode at the colchicine site and to assess drug-likeness. Results: Exclusively, compounds bearing a trimethoxyphenyl group showed antiproliferative activity in the submicromolar range, thus identifying it as a structural requirement. The most potent compound (2) reached double-digit nanomolar IC50 values (67\u2013104 nM) across multiple cancer cell lines. Microscopy confirmed intracellular disruption of microtubule polymerization. Unlike colchicine, these compounds did not induce canonical mitotic arrest but instead triggered apoptotic cell death. In silico analyses supported binding at the colchicine site and revealed favorable predicted pharmacokinetic properties. Conclusions: The naphthalene sulfonamides described herein demonstrate potent antiproliferative activity through a distinct mechanism compared to colchicine, and their favorable in silico profiles position them as promising candidates for further development as antitumor agents.<\/jats:p>","DOI":"10.3390\/pharmaceutics18060733","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T05:56:31Z","timestamp":1781675791000},"page":"733","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Antimitotic Naphthalene Sulfonamides Are Potent Antitumor Agents Acting Differently from Colchicine"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8768-2507","authenticated-orcid":false,"given":"Miguel","family":"Mar\u00edn","sequence":"first","affiliation":[{"name":"Laboratorio de Qu\u00edmica Org\u00e1nica y Farmac\u00e9utica, Departamento de Ciencias Farmac\u00e9uticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain"},{"name":"Centro de Investigaci\u00f3n de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ra\u00fal","family":"Fuentes-Mart\u00edn","sequence":"additional","affiliation":[{"name":"Laboratorio de Qu\u00edmica Org\u00e1nica y Farmac\u00e9utica, Departamento de Ciencias Farmac\u00e9uticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain"},{"name":"Centro de Investigaci\u00f3n de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baldomero","family":"S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Laboratorio de Qu\u00edmica Org\u00e1nica y Farmac\u00e9utica, Departamento de Ciencias Farmac\u00e9uticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain"},{"name":"Centro de Investigaci\u00f3n de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8301-2784","authenticated-orcid":false,"given":"Laura","family":"Gallego-Yerga","sequence":"additional","affiliation":[{"name":"Laboratorio de Qu\u00edmica Org\u00e1nica y Farmac\u00e9utica, Departamento de Ciencias Farmac\u00e9uticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain"},{"name":"Centro de Investigaci\u00f3n de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1433-1612","authenticated-orcid":false,"given":"Rafael","family":"Pel\u00e1ez","sequence":"additional","affiliation":[{"name":"Laboratorio de Qu\u00edmica Org\u00e1nica y Farmac\u00e9utica, Departamento de Ciencias Farmac\u00e9uticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain"},{"name":"Centro de Investigaci\u00f3n de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS), Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, 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