{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T16:39:32Z","timestamp":1790008772667,"version":"4.0.1"},"reference-count":85,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Late-stage metastatic cutaneous melanoma (MCM) and neuroblastoma (NB) are the most aggressive skin and childhood cancers with survival rates of &lt;50%, mainly due to the emergence of resistance to available drugs, thus requiring an urgent solution. Quaternary phosphonium salts (QPSs) can exhibit strong anticancer effects, regardless of the developed resistance. Triphenyl (1) and diphenyl (3 and 4) phosphonium salts were synthesized, treating commercial triphenyl phosphine and synthesizing 11-diphenylphosphanyl-undecan-1-ol (2), respectively, with benzyl bromide. Upon full characterization, they were tested, for the first time, on MeTRAV (BRAFV600D) and MeOV (BRAFV600E) vemurafenib (PLX)-resistant MCM cells, etoposide (ETO)-sensitive (HTLA 230) and multidrug resistant (MDR) (HTLA ER) NB cells, non-tumorigenic human keratinocytes (HaCaT), and mouse embryonic fibroblasts (3T3), as well as red blood cells (RBCs). Viability of MeTRAV cells was decreased to 44.8% by administration of 1 (100 \u00b5M), in intermediate-time (48 h) treatments, while short-time exposure (24 h) to 3 (\u226575 \u00b5M) and 4 (\u226550 \u00b5M) was sufficient to reduce their viability to 33.6 and 32.2%. Viability of MeOV was decreased under 50% with 5 \u00b5M concentrations of 1 and 25 \u00b5M of 3 and 4, While cells were exterminated (26.9, 20.6, and 21.8%) with higher concentrations after 48 h exposure. Collectively, 1 was the better performing compound (IC50 = 6.4 \u00b5M, 48 h). Viability of HTLA ER cells was decreased under 50% upon 72 h administrations of 1 at concentrations \u2265 50 \u00b5M, 48 h (\u226575 \u00b5M) and 72 h (\u226550 \u00b5M) of 3, and after 72 h (\u226575 \u00b5M) of 4, but 72 h exposure and high concentrations of all compounds were necessary for their extermination (31.2, 28.7, and 29.7%). Viability of HTLA 230 cells was not &lt;50% when 1 and 4 were administered for only 24 h, while their viability was &lt;50% after administration of 3 at all times of exposure. At high concentrations, all compounds exterminated cells (33.6, 25.3%, 1, 48\u201372 h; 38.6, 30.2, and 24.7%, 3, 24\u201372 h; 33.2%, 4, 72 h). The best-performing compounds were 1 (IC50 = 4.0 \u00b5M, HTLA 230) and 3 (IC50 = 27.8 \u00b5M, HTLA ER) at 72 h exposure. The cytotoxic effects of compound 4 on MeTRAV cells, when exposed to 24\/48 h treatments, were comparable to those of PLX on the same cells in 72 h treatments. Compound 1, in shorter 48 h treatments of PLX-R MeOV, was 2.5-fold more cytotoxic than PLX in 72 h ones. All compounds were not cytotoxic to 3T3 cells at all times of exposure; they had low cytotoxicity to HaCaT cells in 24 and 48 h treatments and were slightly cytotoxic to RBCs in 24 h ones. Compound 1 could be a promising platform to develop new intermediate-time therapies for PLX-R MeOV cells, while 4 could be used to develop 24 and 48 h treatments for PLX-R MeTRAV cells. Also, all compounds could be developed as new treatment options for both ETO-sensitive and MDR late-stage HR-NB cells, being even more effective than ETO by 1.2, 2.0, and 1.3 times (HTLA 230) and 3.2, 4.7, and 3.2 times (HTLA ER). All compounds have the potential to be developed as adjuvants in already existing anticancer cocktails to treat MCM and\/or NB.<\/jats:p>","DOI":"10.3390\/ijms27073170","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T13:23:17Z","timestamp":1774963397000},"page":"3170","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Quaternary Phosphonium Salts Outperformed Vemurafenib (PLX) and Etoposide Against BRAFV600D,V600E PLX-Resistant Melanoma and MDR Neuroblastoma, Exhibiting No\/Low Toxicity on 3T3\/HaCaT Cells"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4630-4371","authenticated-orcid":false,"given":"Silvana","family":"Alfei","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Genoa, Viale Cembrano, 16148 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Grazia","family":"Signorello","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Genoa, Viale Cembrano, 16148 Genoa, Italy"},{"name":"Biochemistry Laboratory, Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2384-0072","authenticated-orcid":false,"given":"Sara","family":"Tirendi","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine (DIMES), University of Genova, Via Alberti L.B., 16132 Genoa, Italy"},{"name":"Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), 56122 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7390-916X","authenticated-orcid":false,"given":"Elaheh","family":"Khaledizadeh","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine (DIMES), University of Genova, Via Alberti L.B., 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Giordani","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Genoa, Viale Cembrano, 16148 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Reggio","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Therapies in Oncology, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3056-6569","authenticated-orcid":false,"given":"Barbara","family":"Marengo","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine (DIMES), University of Genova, Via Alberti L.B., 16132 Genoa, Italy"},{"name":"IRCCS Azienda Ospedaliera Metropolitana, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5003-7333","authenticated-orcid":false,"given":"Cinzia","family":"Domenicotti","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine (DIMES), University of Genova, Via Alberti L.B., 16132 Genoa, Italy"},{"name":"IRCCS Azienda Ospedaliera Metropolitana, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/S0140-6736(23)00821-8","article-title":"Cutaneous Melanoma","volume":"402","author":"Long","year":"2023","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"(2012). 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