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Novel triazole-linked 5-amidino benzimidazoles as potent multi-target inhibitors for the treatment of non-small cell lung cancer

Lung cancer remains by far the single most common cause of cancer-related mortality worldwide. Multi-targeted therapy seems to be the next step of advancement in the treatment of lung cancer1. The benzimidazole nucleus is an important pharmacophore in medicinal chemistry due to its wide range of biological activity such as anticancer, antimicrobial, antiviral, anti- inflammatory and antioxidant2. Besides being recognized as DNA binding agents benzimidazoles have been identified as potent inhibitors of protein kinases. Furthermore, the 1, 2, 3-triazole skeleton with a variety of biological activities, has found application as a linker between two pharmacophores and a bioisostere of the amide bond3. A series of novel triazole-linked 5- amidino benzimidazoles were synthesized as potential antitumor compounds. Some representatives have shown selective inhibitory effects against non-small cell lung carcinoma (A- 549) and cervical carcinoma (HeLa). Further biological evaluations of the most selective compounds provided support for different regulation of cellular signaling. While cytostatic effect of the most selective imidazoline benzimidazole may be ascribed to down-regulation of multiple kinases including TGM2, CDK9, SK1 and p38 MAPK, as well as abrogation of p35 activity in A549 cells, the N-isopropylamidine benzimidazole did not exhibit profound effect on the expression levels of either TGM2 or CDK9. Instead, antiproliferative effect of this compound on A549 cells could be attributed to reduction of SK1 activity concomitant with decrease in p38 MAPK activity (Figure 1).

amidino benzimidazoles ; 1, 2, 3-triazoles ; lung carcinoma ; p38MAPK

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