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	Basudeb Maji, Krishan Kumar, Mangesh Kaulage, K Muniyappa, Santanu Bhattacharya
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 16 Pg. 6973-88 (Aug 28 2014) ISSN: 1520-4804 [Electronic] United States
PMID	25062468 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Benzimidazoles Carbazoles Enzyme Inhibitors Ligands carbazole benzimidazole Telomerase
Topics	Antineoplastic Agents (chemical synthesis, chemistry, metabolism, pharmacology) Benzimidazoles (chemistry) Carbazoles (chemistry) Cell Death (drug effects) Cell Line, Tumor Chemistry Techniques, Synthetic Circular Dichroism Drug Design Drug Evaluation, Preclinical (methods) Drug Screening Assays, Antitumor Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology) G-Quadruplexes Humans Inhibitory Concentration 50 Ligands Molecular Dynamics Simulation Molecular Structure Neoplasms (drug therapy, genetics, pathology) Spectrometry, Fluorescence Telomerase (antagonists & inhibitors) Telomere (genetics)

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