{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:58:47Z","timestamp":1787029127760,"version":"build-2736575974"},"reference-count":73,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science, Technological Development and Innovation, Republic of Serbia","award":["451-03-136\/2025-03\/200161"],"award-info":[{"award-number":["451-03-136\/2025-03\/200161"]}]},{"name":"Ministry of Science, Technological Development and Innovation, Republic of Serbia","award":["451-03-137\/2025-03\/200161"],"award-info":[{"award-number":["451-03-137\/2025-03\/200161"]}]},{"name":"Institute for Oncology and Radiology of Serbia","award":["451-03-136\/2025-03\/200043"],"award-info":[{"award-number":["451-03-136\/2025-03\/200043"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Telmisartan, an angiotensin II type 1 receptor (AT1R) antagonist, possesses cytotoxic activity towards BRAF-mutated melanoma cell lines. However, its antihypertensive effects limit its use in the population of normotensive patients. To mitigate this shortcoming, a group of eight telmisartan\u2013amino acid conjugates, designed to have reduced or no AT1R affinity with enhanced cellular uptake, were synthesized by the coupling reaction in yields ranging from 34% to 60%. Their cytotoxicity was tested on BRAF V600E-mutated melanoma cell lines (A375 and 518A2), and compounds 1, 3, and 8 stood out as the best candidates. These three compounds were also tested on the vemurafenib-resistant (A375R) and normal (HaCaT and MRC-5) cell lines, and compound 8 showed better cytotoxicity (IC50 = 8.84 \u00b1 1.24 \u00b5M) and selectivity (&gt;3.50) when compared to telmisartan (IC50 = 29.23 \u00b1 3.88, selectivity &gt; 2.40). The cellular uptake of compounds 1 and 8 was significantly higher than telmisartan, with substantial accumulation in the membrane and nuclear compartments. Unlike telmisartan, compounds 1, 3, and 8 did not inhibit angiotensin II-induced Ca2+ signaling, which indicates diminished AT1R binding. All three compounds induced cell cycle arrest and disrupted mitochondrial morphology and membrane potential. These findings highlight their potential as non-antihypertensive telmisartan derivatives for melanoma therapy.<\/jats:p>","DOI":"10.3390\/molecules31010125","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T13:30:52Z","timestamp":1767187852000},"page":"125","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Newly Synthesized Telmisartan\u2013Amino Acid Conjugates Exhibit Enhanced Cytotoxic Effects in Malignant Melanoma Cells"],"prefix":"10.3390","volume":"31","author":[{"given":"Dragana","family":"Vukadinovi\u0107","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of Belgrade\u2014Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia"},{"name":"Department for Pharmacy, Military Medical Academy, Crnotravska 17, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0781-8433","authenticated-orcid":false,"given":"Ana","family":"Damjanovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miodrag","family":"Vukovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivera","family":"\u010cudina","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of Belgrade\u2014Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1430-8682","authenticated-orcid":false,"given":"Jelena","family":"Grahovac","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5086-9017","authenticated-orcid":false,"given":"Vladimir","family":"Dobri\u010di\u0107","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of Belgrade\u2014Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"key":"ref_1","unstructured":"National Cancer Institute (2025, November 15). 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