title: Design and synthesis of new benzimidazole-carbazole conjugates for the stabilization of human telomeric DNA, telomerase inhibition, and their selective action on cancer cells.
abstract: Cell-permeable small molecules that enhance the stability of the G-quadruplex (G4) DNA structures are currently among the most intensively pursued ligands for inhibition of the telomerase activity. Herein we report the design and syntheses of four novel benzimidazole-carbazole conjugates and demonstrate their high binding affinity to G4 DNA. S1 nuclease assay confirmed the ligand mediated G-quadruplex DNA protection. Additional evidence from Telomeric Repeat Amplification Protocol (TRAP-LIG) assay demonstrated efficient telomerase inhibition activity by the ligands. Two of the ligands showed IC50 values in the sub-micromolar range in the TRAP-LIG assay, which are the best among the benzimidazole derivatives reported so far. The ligands also exhibited cancer cell selective nuclear internalization, nuclear condensation, fragmentation, and eventually antiproliferative activity in long-term cell viability assays. Annexin V-FITC/PI staining assays confirm that the cell death induced by the ligands follows an apoptotic pathway. An insight into the mode of ligand binding was obtained from the molecular dynamics simulations.
authors: Department of Organic Chemistry, Indian Institute of Science , Bangalore, Karnataka 560 012, India.
authors: Basudeb
authors: B
authors: Maji
authors: Krishan
authors: K
authors: Kumar
authors: Mangesh
authors: M
authors: Kaulage
authors: K
authors: K
authors: Muniyappa
authors: Santanu
authors: S
authors: Bhattacharya
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry*; D002227:Carbazoles / Q000737:chemistry*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D002942:Circular Dichroism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054856:G-Quadruplexes; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013050:Spectrometry, Fluorescence; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D002227:Carbazoles; D004791:Enzyme Inhibitors; D008024:Ligands; C041514:carbazole; C031000:benzimidazole; D019098:Telomerase