Antiproliferative and Uncoupling Effects of Delocalized, Lipophilic, Cationic Gallic Acid Derivatives on Cancer Cell Lines. Validation in Vivo in Singenic Mice

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• 作者：Jos茅 A. Jara ; Vicente Castro-Castillo ; Jorge Saavedra-Olavarr铆a ; Liliana Peredo ; Mario Pavanni ; Fabi谩n Ja帽a ; Mar铆a Eugenia Letelier ; Eduardo Parra ; Mar铆a In茅s Becker ; Antonio Morello ; Ulrike Kemmerling ; Juan Diego Maya ; Jorge Ferreira
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2440-2454
• 全文大小：651K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

Tumor cells principally exhibit increased mitochondrial transmembrane potential (螖唯_m) and altered metabolic pathways. The therapeutic targeting and delivery of anticancer drugs to the mitochondria might improve treatment efficacy. Gallic acid exhibits a variety of biological activities, and its ester derivatives can induce mitochondrial dysfunction. Four alkyl gallate triphenylphosphonium lipophilic cations were synthesized, each differing in the size of the linker chain at the cationic moiety. These derivatives were selectively cytotoxic toward tumor cells. The better compound (TPP⁺C₁₀) contained 10 carbon atoms within the linker chain and exhibited an IC₅₀ value of approximately 0.4鈥?.6 渭M for tumor cells and a selectivity index of approximately 17-fold for tumor compared with normal cells. Consequently, its antiproliferative effect was also assessed in vivo. The oxygen consumption rate and NAD(P)H oxidation levels increased in the tumor cell lines (uncoupling effect), resulting in a 螖唯_m decrease and a consequent decrease in intracellular ATP levels. Moreover, TPP⁺C₁₀ significantly inhibited the growth of TA3/Ha tumors in mice. According to these results, the antineoplastic activity and safety of TPP⁺C₁₀ warrant further comprehensive evaluation.