Design and synthesis of benzimidazole derivatives as apoptosis-inducing agents by targeting Bcl-2 protein
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Date
2023
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Abstract
Bcl-2, an anti-apoptotic protein, is a well-known and appealing cancer therapy target. Novel series of benzimidazole derivatives were synthesized and tested for their activity as Bcl-2 inhibitors on T98G glioblastoma, PC3 prostate, MCF-7 breast, and H69AR lung cancer cells. MTT assay was used to evaluate the cytotoxic effect. PI Annexin V Apoptosis Detection Kit was used to detect apoptosis. Expression levels of the Bcl-2 protein were examined by the Western blot analysis and qRT-PCR. All synthesized benzimidazole derivatives exhibited a cytotoxic effect on cancer cells with IC50 values in the range of 25.2–88.2 µg/mL. Among all derivatives, compounds C1 and D1 demonstrated a higher cytotoxic effect on cancer cells with IC50 values < 50 µg/mL, while a lower cytotoxic effect against human embryonic kidney cells with IC50 values of > 100 µg/mL. C1 and D1 caused a significant increase in the percentage of apoptotic cells in all types of cancer cell cells and both Bcl-2 mRNA and protein levels were significantly reduced. These results suggest that the novel benzimidazole derivatives may be candidates for apoptosis-inducing agents in cancer treatment by targeting anti-Bcl-2 proteins in cancer cells. Graphical abstract: [Figure not available: see fulltext.]. © 2022, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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Antineoplastic Agents , Apoptosis , Benzimidazoles , Cell Line, Tumor , Cell Proliferation , Humans , 2 (5,6 dichloro 2 ethyl 1h benzimidazol 1 yl) n' [4 oxo 3 phenyl 1,3 thiazolidin 2 ylidene] acetohydrazide , 2 [(5,6 dichloro 2 ethyl 1h benzimidazol 1 yl) acetyl] n phenylhydrazine carboamide , 5 [(5,6 dichloro 2 ethyl 1h benzimidazol 1 yl) methyl] 4 phenyl 4h 1,2,4 triazol 3 ol , 5 [(5,6 dichloro 2 ethyl 1h benzimidazol 1 yl) methyl] n phenyl 1,3,4 thiadiazol 2 amine , 5 [(5,6 dichloro 2 ethyl 1h benzimidazol 1 yl)methyl] n phenyl 1,3,4 oxadiazol 2 amine , antineoplastic agent , benzimidazole derivative , messenger RNA , protein bcl 2 , unclassified drug , antineoplastic agent , benzimidazole derivative , antineoplastic activity , apoptosis , Article , clinical effectiveness , controlled study , cytotoxicity , drug design , drug effect , drug efficacy , drug mechanism , drug response , drug structure , drug synthesis , H69AR cell line , human , human cell , IC50 , MCF-7 cell line , MTT assay , PC3 cell line , prostate cancer cell line , protein expression , protein targeting , real time polymerase chain reaction , T98G cell line , Western blotting , apoptosis , cell proliferation , tumor cell line