Novel indole-guanidine hybrids as potential anticancer agents: Design, synthesis and biological evaluation

Based on the scaffold hybridization strategy, twenty-four indole-guanidines were designed and synthesized. Subsequently, anti-proliferative activity against various cancer cells indicated that most of these hybrids exhibited moderate to high anti-proliferative activity, especially for human hepatoma cell lines. Selectivity investigation showed that these hybrids showed the best selectivity for SMMC-7721 subtype in human hepatoma cells. Particularly, (E)-3-((2-(N-pentylcarbamimidoyl)hydrazono)methyl)-1H-indol-5-yl 4-methylbenzoate (19) and (E)-3-((2-(N-pentylcarbamimidoyl)hydrazono)methyl)-1H-indol-5-yl 4-methoxybenzoate (22) exhibited potent inhibition against SMMC-7721 cells with IC50 values of 0.057 mu M and 0.042 mu M, respectively, far outperforming that of Sorafenib. Meanwhile, hybrids 19 and 22 exhibited no significant cytotoxicity against normal cells such as HEK293 cells and HEK293T cells. Moreover, further investigations indicated that hybrid 22 effectively induced apoptosis, arrested the cell cycle at S phase, and selectively down regulated expression of p-STAT3, JAK2 and BRAF in SMMC-7721 cells in a dose-dependent manner. Molecular docking indicated that hybrid 22 exhibited high affinity with STAT3 and BRAF. In summary, hybrid 22 was developed as a potential and effective anti-hepatoma candidate, which was worthy of further investigation.

Automated summary

Based on the scaffold hybridization strategy, twenty-four indole-guanidines were designed and synthesized. Most of these hybrids exhibited moderate to high anti-proliferative activity against various cancer cells, especially human hepatoma cell lines. Selectivity investigation showed that the hybrids had the best selectivity for the SMMC-7721 subtype in human hepatoma cells. Particularly, compound 22 demonstrated potent inhibition against SMMC-7721 cells, inducing apoptosis and cell cycle arrest in a dose-dependent manner, while down-regulating the expression of specific proteins.