Synthesis of Novel Mitochondria-Targeted Tranilast Derivatives with a Triphenylphosphonium Fragment in the Side Chain Exhibiting Enhanced In Vitro Antitumor Activity

N-3,4-dimethoxycinnamoylanthranilic acid (the active ingredient of the drug Tranilast) is an amide of anthranilic acid and 3,4-dimethoxycinnamic acid. This drug has been used in Japan and South Korea since 1982 for the treatment of bronchial asthma. Subsequent studies have shown that Tranilast is effective in the treatment of a wide range of diseases, including fibrosis, proliferative disorders, autoimmune disorders and exhibits promising antitumor activity. But its clinical application is limited by low bioavailability and non-selective cellular localization. As a promising approach to overcome these drawbacks, we employed conjugation of Tranilast with the lipophilic cation triphenylphosphonium (TPP⁺), which ensures targeted delivery of the compound to mitochondria – the primary source of reactive oxygen species. We have developed an efficient method for the synthesis of two previously unknown amide derivatives of Tranilast bearing a TPP⁺-group in the side chain linked via C-6-alkyl or dipeptide linkers. The synthesis involved amidation of Tranilast with aminohexanol, mesylation of the terminal hydroxyl group, transformation of the mesylate into the azide by reaction with NaN₃. The azide group was reduced to an amine using PPh₃ and reacted with alkyl triphenylphosphonium salts. The structures were confirmed by 1D- and 2D-NMR spectroscopy. Cytotoxic activity was studied in vitro against six human cancer cell lines (MCF-7, MDA-MB-231, A549, K562, Jurkat, SH-SY5Y) and normal HEK293T cells. It was found that the Tranilast exhibited no cytotoxicity (IC₅₀ > 100 µM), whereas its amide TPP⁺-derivatives demonstrated antitumor activity against all tested cell lines in the low micromolar range (IC₅₀ = 4.58–14.31 µM).