Design, synthesis and biological evaluation of new β-carboline-bisindole compounds as DNA binding, photocleavage agents and topoisomerase I inhibitors

• DOI: 10.1016/j.ejmech.2017.10.054
• Publication Date: 2017-10-23T20:16:39Z
• Authors: Jeshma Kovvuri; Burri Nagaraju; V. Lakshma Nayak; Ravikumar Akunuri; M.P. Narasimha Rao; Ayyappan Ajitha; Narayan Nagesh; Ahmed Kamal
• Keywords: 0301 basic medicine; Binding Sites; Indoles; Photosensitizing Agents; Dose-Response Relationship, Drug; Molecular Structure; Antineoplastic Agents; DNA, Neoplasm; 3. Good health; Molecular Docking Simulation; Structure-Activity Relationship; 03 medical and health sciences; DNA Topoisomerases, Type I; Cell Line, Tumor; Drug Design; Humans; Drug Screening Assays, Antitumor; Topoisomerase I Inhibitors; Carbolines; Cell Proliferation

A series of new β-carboline-bisindole compounds were designed, synthesized and evaluated for their antiproliferative activity against human cancer cell lines, such as A549 (lung cancer), DU-145 (prostate cancer), HeLa (cervical cancer) and MCF-7 (breast cancer). All the compounds exhibited considerable antiproliferative activity. Among them, compounds 7g and 7r exhibited significant antiproliferative activity against DU-145 cells with IC50 values 1.86 and 1.80 μM respectively. Further, these compounds effectively inhibit DNA topoisomerase I activity and can also cleave the pBR322 plasmid upon irradiation with UV light. In addition, Annexin V-FITC assay suggested that these compounds induced apoptosis in DU- 145 cell line (prostate cancer). To know the binding mode of these compounds with DNA, spectroscopic studies were also carried out. These new compounds were showing a unique mode of binding with DNA, both biophysical studies such as UV-Visible, fluorescence, circular dichroism and molecular docking studies revealed that the β-carboline-bisindole compounds exhibit combilexin type of interaction with DNA.