title: N'-((2-(6-bromo-2-oxo-2H-chromen-3-yl)-1H-indol-3-yl)methylene)benzohydrazide as a probable Bcl-2/Bcl-xL inhibitor with apoptotic and anti-metastatic potential.
abstract: A wide number of marketed drugs and drug candidates in cancer clinical development contain halogen substituents. The aim of the present study was to synthesize a series of halogen incorporated indole-coumarin hybrid schiff bases - N'-((2-(2-oxo-2H-chromen-3-yl)-1H-indol-3-yl)methylene)benzohydrazides and to investigate their apoptotic and anti-migratory potential in human breast adenocarcinoma cells as well as to examine their Bcl-2 and Bcl-xL protein binding ability via in silico docking. Hybrid 5g with a bromine atom in position-7 of coumarin ring displayed significant dose dependent cytotoxic activity with high selectivity to MCF-7 cells in MTT assay. Cell cycle progression analysis of 5g treated cells using flow cytometer exhibited a cell cycle arrest in the S phase and accumulation of cells in the subG1 phase. The apoptotic mode of cell death induced by 5g was further confirmed by Annexin-V staining assay. The wound healing assay revealed a profound impairment in the migration of MCF-7 cells presumably due to down-regulation of Bcl-2 and Bcl-xL proteins induced by 5g as observed in immunoblotting analysis. SAR studies of these hybrid molecules based on cell viability and docking were also probed. The most active pharmacophore 5g was found to bind favourably to Bcl-2 and Bcl-xL in docking simulation analysis suggesting it to be a probable small molecule Bcl-2/Bcl-xL inhibitor and a potential lead for breast cancer chemotherapy with apoptotic and anti-metastatic properties.
authors.affiliation: Department of Chemistry, Manipal Institute of Technology, Manipal University, India.
authors.forename: Pooja R
authors.initials: PR
authors.lastname: Kamath
authors.affiliation: Department of Chemistry, Manipal Institute of Technology, Manipal University, India. Electronic address: dhanyadss3@gmail.com.
authors.forename: Dhanya
authors.initials: D
authors.lastname: Sunil
authors.affiliation: Department of Atomic and Molecular Physics, Manipal Institute of Technology, Manipal University, India.
authors.forename: A Abdul
authors.initials: AA
authors.lastname: Ajees
authors.affiliation: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, India.
authors.forename: K S R
authors.initials: KS
authors.lastname: Pai
authors.affiliation: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, India.
authors.forename: Shubankar
authors.initials: S
authors.lastname: Biswas
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: D006834:Hydrazines; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein
keywords: Apoptosis; Bcl-2/Bcl-xL; Cell cycle; Cytotoxicity; Hybrid schiff base; Metastasis