Novel diindoloazepinone derivatives as DNA minor groove binding agents with selective topoisomerase I inhibition: Design, synthesis, biological evaluation and docking studies

• Published in: Bioorganic chemistry Vol. 99; pp. 103629 - 103646
• Main Authors: Kadagathur, Manasa, Devi, G. Parimala, Grewal, Preeti, Sigalapalli, Dilep Kumar, Makhal, Priyanka N., Banerjee, Uttam Chand, Bathini, Nagendra Babu, Tangellamudi, Neelima D.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.06.2020; Elsevier
• Subjects: Anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Azepines - chemical synthesis; Azepines - chemistry; Azepines - pharmacology; Binding Sites - drug effects; Biochemistry & Molecular Biology; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Chemistry; Chemistry, Organic; Diindoloazepinone; DNA minor groove binding; DNA Topoisomerases, Type I - metabolism; DNA, Neoplasm - drug effects; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Indoloazepinone; Life Sciences & Biomedicine; Molecular Docking; Molecular Docking Simulation; Molecular Structure; Physical Sciences; Science & Technology; Selective topoisomerase I inhibitor; Structure-Activity Relationship; Topoisomerase I Inhibitors - chemical synthesis; Topoisomerase I Inhibitors - chemistry; Topoisomerase I Inhibitors - pharmacology; Indoloazepinone; Selective topoisomerase I inhibitor; DNA minor groove binding; Diindoloazepinone; Molecular Docking; Anticancer activity; HYMENIALDISINE; APOPTOSIS; ANALOGS; ANTITUMOR; DISCOVERY; MOLECULES; CIRCULAR-DICHROISM; LIGANDS; PROPIDIUM IODIDE; CALF THYMUS DNA
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103629

[Display omitted] •New diindoloazepinone derivatives were designed and synthesized.•Compound 11 manifested promising cytotoxicity against A549 with IC50 value of 4.2 µM.•11 induced early apoptosis, damaged mitochondrial membrane potential, cell cycle arrest at sub-G1 phase.•11 showed DNA-minor groove binding and selective topoisomerase I inhibition.•The in vitro results were supported by molecular docking studies. We present here-in the molecular design and chemical synthesis of a novel series of diindoloazepinone derivatives as DNA minor groove binding agents with selective topoisomerase I inhibition. The in vitro cytotoxicity of the synthesized compounds was evaluated against four human cancer cell lines including DU143, HEPG2, RKO and A549 in addition to non-cancerous immortalized human embryonic kidney cells (HEK-293). Compound 11 showed significant cytotoxicity against all the four human cancer cell lines with IC50 values ranging from 4.2 to 6.59 μM. 11 was also found to display 13-fold selective cytotoxicity towards A549 cancerous cells compared to the non-cancerous cell lines (HEK-293). The decatenation, DNA relaxation and intercalation assays revealed that the investigational compounds 10 and 11 act as highly selective inhibitors of Topo-I with DNA minor groove binding ability which was also supported by the results obtained from circular dichroism (CD), UV-visible spectroscopy and viscosity studies. Apoptosis induced by the lead 11 was observed using morphological observations, AO/EB and DAPI staining procedures. Further, dose-dependent increase in the depolarization of mitochondrial membrane was also observed through JC-1 staining. Annexin V-FITC/PI assay confirmed that 11 induced early apoptosis. Additionally, cell cycle analysis indicated that the cells were arrested at sub-G1 phase. Gratifyingly, in silico studies demonstrated promising interactions of 11 with the DNA and Topo I, thus supporting their potential DNA minor groove binding property with relatively selective Topo I inhibition compared to Topo II.