title: Antiproliferative activity of bicyclic benzimidazole nucleosides: synthesis, DNA-binding and cell cycle analysis.
abstract: An efficient route was developed for synthesis of bicyclic benzimidazole nucleosides from readily available d-glucose. The key reactions were Vörbruggen glycosylation and ring closing metathesis (RCM). Primarily, to understand the mode of DNA binding, we performed a molecular docking study and the binding was found to be in the minor groove region. Based on the proposed binding model, UV-visible and fluorescence spectroscopic techniques using calf thymus DNA (CT-DNA) demonstrated a non-intercalative mode of binding. Antiproliferative activity of nucleosides was tested against MCF-7 and MDA-MB-231 breast cancer cell lines and found to be active at low micromolar concentrations. Compounds and displayed significant antiproliferative activity as compared to and with the reference anticancer drug, doxorubicin. Cell cycle analysis showed that nucleoside induced cell cycle arrest at the S-phase. Confocal microscopy has been performed to validate the induction of cellular apoptosis. Based on these findings, such modified bicyclic benzimidazole nucleosides will make a significant contribution to the development of anticancer drugs.
authors.affiliation: Department of Chemistry, Savitribai Phule Pune University (formerly University of Pune), Pune-411007, India. vsshinde@chem.unipune.ac.in.
authors.forename: Vyankat A
authors.initials: VA
authors.lastname: Sontakke
authors.affiliation: Department of Chemistry, Savitribai Phule Pune University (formerly University of Pune), Pune-411007, India. vsshinde@chem.unipune.ac.in.
authors.forename: Pravin P
authors.initials: PP
authors.lastname: Lawande
authors.affiliation: Department of Chemistry, Savitribai Phule Pune University (formerly University of Pune), Pune-411007, India. vsshinde@chem.unipune.ac.in.
authors.forename: Anup N
authors.initials: AN
authors.lastname: Kate
authors.affiliation: Department of Chemistry, Savitribai Phule Pune University (formerly University of Pune), Pune-411007, India. vsshinde@chem.unipune.ac.in.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Khan
authors.affiliation: Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune-411007, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Joshi
authors.affiliation: Department of Chemistry, Savitribai Phule Pune University (formerly University of Pune), Pune-411007, India. vsshinde@chem.unipune.ac.in.
authors.forename: Anupa A
authors.initials: AA
authors.lastname: Kumbhar
authors.affiliation: Department of Chemistry, Savitribai Phule Pune University (formerly University of Pune), Pune-411007, India. vsshinde@chem.unipune.ac.in.
authors.forename: Vaishali S
authors.initials: VS
authors.lastname: Shinde
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004273:DNA, Neoplasm; D009705:Nucleosides; C031000:benzimidazole