Newly Synthesized Telmisartan-Amino Acid Conjugates Exhibit Enhanced Cytotoxic Effects in Malignant Melanoma Cells

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-amino 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 ± 1.24 µM) and selectivity (>3.50) when compared to telmisartan (IC₅₀ = 29.23 ± 3.88, selectivity > 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.