Conjugation of Triterpenic Acids of Ursane and Oleanane Types with Mitochondria-Targeting Cation F16 Synergistically Enhanced Their Cytotoxicity against Tumor Cells

Abstract

The present work shows the cytotoxic effects of novel conjugates of ursolic, oleanolic, maslinic, and corosolic acids with the penetrating cation F16 on cancer cells (lung adenocarcinoma A549 and H1299, breast cancer cell lines MCF-7 and BT474) and non-tumor human fibroblasts. It has been established that the conjugates have a significantly enhanced toxicity against tumor-derived cells compared to native acids and also demonstrate selectivity to some cancer cells. The toxic effect of the conjugates is shown to be due to ROS hyperproduction in cells, induced by the effect on mitochondria. The conjugates caused dysfunction of isolated rat liver mitochondria and, in particular, a decrease in the efficiency of oxidative phosphorylation, a decrease in the membrane potential, and also an overproduction of ROS by organelles. The paper discusses how the membranotropic- and mitochondria-targeted effects of the conjugates may be related to their toxic effects.

Synthesis and Cytotoxic Activity of Conjugates of Mitochondrial-Directed Cationic Compound F16 with Ursane-Structure Triterpenic Acids Containing a Polyhydroxylated A-ring

“…The bromalkyl esters 8, 9, 13, 17, 18 and conjugates 1-5 were synthesized as previously described [18,19]. The physico-chemical and spectral characteristics of the compounds were in full agreement with the data presented in [19].…”

“…The synthesized conjugates 1-5 were examined for cytotoxic activity against two human lung adenocarcinoma cell lines H1299 and A549 and non-cancerous MEFs (mouse embryonic fibroblasts). The cytotoxicity of the previously synthesized ursolic acid F16derivative 6 was also examined on these cell lines for comparison (Table 1) [18]. From the results presented in the table, it is evident that introducing a terminal cationic fragment into the C-28 side chain of the examined triterpenic acids resulted in significant enhancement of cytotoxicity compared to ursolic acid, regardless of the presence of acetylated or free hydroxyl groups in the A-ring.…”

F16 Hybrids Derived from Steviol or Isosteviol Are Accumulated in the Mitochondria of Tumor Cells and Overcome Drug Resistance

“…In extensions of our previous investigations of triterpenes to diterpenes [12][13][14], we were able to present and investigate cytotoxic derivatives of isosteviol, a stachane-type prepared, which exhibit low EC50 values with good selectivity [9][10][11]. A decrease in the intensity of ADP phosphorylation was also observed for these derivatives.…”

“…Currently, hybrids of pentacyclic triterpene carboxylic acids with a distal-linked, substituted N -methylpyridinium radical, so-called F16 derivatives [ 7 , 8 ], can also be prepared, which exhibit low EC 50 values with good selectivity [ 9 , 10 , 11 ]. A decrease in the intensity of ADP phosphorylation was also observed for these derivatives.…”

Toxic Effects of Penetrating Cations

“…F16 conjugates with ursolic, oleanolic, maslinic, and corosolic acids, which show increased toxicity to cancer cells. This toxicity is also due to an increase in ROS that occurs during the action of the conjugates on mitochondria [68]. Work is underway to study the anticancer toxicity of F16 derivatives; for example, it has been shown that 5-Br-7MeF16 (5BMF) has a low IC50 of ∼50 nM (to H2228 cells) and a high cancer to normal cell selectivity index of 225 [69].…”