Synthesis and cytotoxic evaluation of F16 derivatives pentacyclic triterpenoid acids possessing a polyhydroxylated ring A

Abstract Pentacyclic triterpenoid acids bearing a polyhydroxylated A ring have been found in many plants and are of interest for their biological properties, including antitumor activity. The present article reports on the design and synthesis of a series of conjugates of a cationic mitochondria-targeted compound, 4-(1-H-indol-3-ylvinyl)-N-methylpyridinium iodide (F16), with maslinic, corosolic, and asiatic acids and with a tri-hydroxylated analogue of betulinic acid. In the new hybrid compounds, the triterpenoids bearing a polyhydroxylated ring A were linked to the cationic fragment F16 in the C-28 side chain through a butyl spacer. The results of in vitro bioscreening in two human tumor cell lines (H1299 and A549) and noncancer fibroblasts (MEFs) revealed that all the studied conjugates demonstrated a significantly stronger antitumor effect than the original natural triterpenoid acids. In particular, the antitumor activity of the corosolic acid conjugate against A549 and H1299 cell lines was 36 and 24 times higher than the activity of ursolic acid. Conjugates of oxygenated triterpenoids containing hydroxyl or acetyl groups at the C-2 atom or C-1/C-2 atoms of the triterpene core exhibited a slight decrease in antitumor activity compared to the corresponding F16-derivatives of betulinic, ursolic and oleanolic acids. Among the studied compounds, acceptable selectivity in relation to tumor and non-malignant cell lines was shown only by the F16 derivatives of the maslinic and asiatic acids, since they were not the active agents against fibroblasts MEFs within the assay.