Design and synthesis of benzimidazole derivatives as apoptosis-inducing agents by targeting Bcl-2 protein

Ilhan S.Çamli Pulat Ç.Oguz F.Bektaş H.Menteşe E.Atmaca H.2024-07-222024-07-22202313811991http://akademikarsiv.cbu.edu.tr:4000/handle/123456789/11885Bcl-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.EnglishAntineoplastic AgentsApoptosisBenzimidazolesCell Line, TumorCell ProliferationHumans2 (5,6 dichloro 2 ethyl 1h benzimidazol 1 yl) n' [4 oxo 3 phenyl 1,3 thiazolidin 2 ylidene] acetohydrazide2 [(5,6 dichloro 2 ethyl 1h benzimidazol 1 yl) acetyl] n phenylhydrazine carboamide5 [(5,6 dichloro 2 ethyl 1h benzimidazol 1 yl) methyl] 4 phenyl 4h 1,2,4 triazol 3 ol5 [(5,6 dichloro 2 ethyl 1h benzimidazol 1 yl) methyl] n phenyl 1,3,4 thiadiazol 2 amine5 [(5,6 dichloro 2 ethyl 1h benzimidazol 1 yl)methyl] n phenyl 1,3,4 oxadiazol 2 amineantineoplastic agentbenzimidazole derivativemessenger RNAprotein bcl 2unclassified drugantineoplastic agentbenzimidazole derivativeantineoplastic activityapoptosisArticleclinical effectivenesscontrolled studycytotoxicitydrug designdrug effectdrug efficacydrug mechanismdrug responsedrug structuredrug synthesisH69AR cell linehumanhuman cellIC50MCF-7 cell lineMTT assayPC3 cell lineprostate cancer cell lineprotein expressionprotein targetingreal time polymerase chain reactionT98G cell lineWestern blottingapoptosiscell proliferationtumor cell lineDesign and synthesis of benzimidazole derivatives as apoptosis-inducing agents by targeting Bcl-2 proteinArticle10.1007/s11030-022-10524-3