Synthesis, cytotoxicity and apoptosis‐inducing activity of novel 1H‐benzo[d]imidazole derivatives of dehydroabietic acid

Abstract

With the expectation of finding new and effective antitumor drugs, a series of novel N-(1H-benzo[d]imidazole-2-yl)-benzamide/benzenesulfonamide derivatives of dehydroabietic acid were synthesized and evaluated for cytotoxic activity against three human cancer cell lines (MCF-7, HeLa, and HepG2 cells) and one human normal hepatocyte cell line (LO2). As a result, a number of derivatives showed moderate to good antitumor activities. Among them, compound 8h exhibited the most potent activities against three cancer cell lines with IC 50 values of 0.87 ± 0.18, 9.39 ± 0.72, and 8.31 ± 0.64 μM, respectively, and was less active to normal hepatocyte LO2 cells. Further mechanism studies revealed that compound 8h could arrest the cell cycle of MCF-7 cells at S phase and induce the apoptosis of MCF-7 cells in ROS-mediated mitochondrial pathway.

Recent Advances on Biological Activities and Structural Modifications of Dehydroabietic Acid

“…However, compared with that of dehydroabietic acid (IC 50 > 50 µM), it was more toxic to normal cells [87]. Compound 79h was also more cytotoxic against normal human LO2 cell (IC 50 : 42.83 ± 3.18 µM) than dehydroabietic acid (IC 50 > 50 µM) [88]. Based on the above results, when compared with the precursor, the bioactivity of some compounds was significantly improved after structural modifications, but their toxicity against normal human cells was also increased.…”

“…In addition, benzenesulfonamide derivatives (79a−79h) had stronger inhibitory activity than benzamide ones (78a−78h). The most cytotoxic compound 79h (IC 50 : 0.87-9.39 µM) can arrest MCF-7 cells in the S phase through ROS-mediated mitochondrial pathway, and finally induce MCF-7 cell apoptosis [88].…”

Imidazoles as Potential Anticancer Agents: An Update on Recent Studies

“…The cytotoxic and apoptosis-inducing activity of benzimidazole derivatives of dehydroabietic acid ( 100 ; see Figure 9 ) were evaluated against MCF-7, HeLa, and HepG2 cancer cell lines and a normal hepatocyte (LO2) cell line by Li et al [ 185 ]. Among these compounds, 216 displayed the highest activity with IC 50 values of 0.87, 9.39, and 8.31 against MCF-7, HeLa, and HepG2 cell lines, respectively.…”

Synthetic and Naturally Occurring Heterocyclic Anticancer Compounds with Multiple Biological Targets

“…In addition to inhibiting tubulin polymerization and arresting G2/M phase of the cell cycle, the compound displayed its cytotoxicity against all the cell lines with IC 50 in the range of 0.25 to 1.5 μM [ 61 ]. Using a similar approach, Li et al synthesized a series of imidazole derivatives of dehydroabietic acid and found them to exhibit antitumor activities via cell cycle arrest at the S phase, activation of intracellular ROS and decrease in mitochondrion potential leading to apoptosis [ 62 ]. Among the series, compound 51 exhibited the highest activity against MCF-7 (0.87 μM), HeLa (9.39 μM), and HepG2 cell lines (8.31 μM) [ 62 ].…”

“…Using a similar approach, Li et al synthesized a series of imidazole derivatives of dehydroabietic acid and found them to exhibit antitumor activities via cell cycle arrest at the S phase, activation of intracellular ROS and decrease in mitochondrion potential leading to apoptosis [ 62 ]. Among the series, compound 51 exhibited the highest activity against MCF-7 (0.87 μM), HeLa (9.39 μM), and HepG2 cell lines (8.31 μM) [ 62 ].…”