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Synthesis and Cytotoxic Activity of Conjugates of Mitochondrial-Directed Cationic Compound F16 with Ursane Structure Triterpenic Acids Containing a Polyhydroxylated A-ring.
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1  Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 Prospekt Oktyabrya, Ufa 450075, Russian Federation
Academic Editor: Julio A. Seijas


Pentacyclic triterpenic acids with an ursane structure, possessing a polyhydroxylated A-ring (such as corosolic and asiatic acids), are found in many medicinal plants and are components of various fruits, berries, and vegetables. These phytochemical substances exhibit a wide range of beneficial biological properties, among which their multifunctional anti-cancer activity and the ability to initiate the mitochondrial pathway of apoptosis in various types of tumor cells are particularly intriguing. Additionally, as an integral part of the diet, these phytochemicals may contribute to the prevention of human oncological diseases. However, the limited penetration of triterpenic acids through cell membranes due to their high hydrophobicity restricts them from reaching their target and exerting the necessary therapeutic effect in animal models. To address this issue, we chemically linked corosolic and asiatic acids, as well as a synthetic polyoxygenated analog of ursolic acid, via an alkyl linker to the cationic mitochondria-directed compound F16 (4-(1H-indol-3-ylvinyl)-N-methylpyridinium iodide). The resulting conjugates were tested for cytotoxic activity against two human lung adenocarcinoma cell lines, H1299 and A549, and non-cancerous mouse embryonic fibroblast (MEF) cells. For comparison, the cytotoxicity of ursolic acid and a previously synthesized F16 derivative of ursolic acid were investigated on these cell lines. The results showed that the conjugation of triterpenic acids with the terminal cationic fragment of F16 in the C-28 side chain significantly amplified (by 27-36 times) cytotoxicity compared to ursolic acid. However, the introduction of additional hydroxyl or acetyl functions into the A-ring led to a slight reduction in cytotoxic effect. For instance, concerning the tumor cell line H1299, the IC50 cytotoxicity values for the F16 conjugates with ursolic, corosolic and asiatic acids were 2.80 μM, 4.01 μM, and 13.51 μM, respectively. Among the studied compounds, the F16 derivative of corosolic acid, compound 4, showed the highest difference in selectivity between tumor A549 cells and mouse fibroblasts MEFs (selectivity index SI = 3.6).

Keywords: Ursolic acid; conjugates; polyhydroxylated ring A; delocalized lypophilic cations; F16; anti-cancer agents.