N′-((2-(6-bromo-2-oxo-2 H -chromen-3-yl)-1 H -indol-3-yl)methylene)benzohydrazide as a probable Bcl-2/Bcl-xL inhibitor with apoptotic and anti-metastatic potential

Pooja R. Kamath, Dhanya Sunil, A. Abdul Ajees, K. S.R. Pai, Shubankar Biswas

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)134-147
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume120
DOIs
Publication statusPublished - 14-09-2016

Fingerprint

Halogens
MCF-7 Cells
Cells
Assays
Bromine
Schiff Bases
Annexin A5
Cell Cycle Checkpoints
S Phase
Immunoblotting
Protein Binding
Pharmaceutical Preparations
Computer Simulation
Wound Healing
Cell Survival
Cell Cycle
Adenocarcinoma
Breast
Cell Death
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

@article{b9e77253947a4cc08fb8f66debef77fa,
title = "N′-((2-(6-bromo-2-oxo-2 H -chromen-3-yl)-1 H -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.",
author = "Kamath, {Pooja R.} and Dhanya Sunil and Ajees, {A. Abdul} and Pai, {K. S.R.} and Shubankar Biswas",
year = "2016",
month = "9",
day = "14",
doi = "10.1021/ar0400995",
language = "English",
volume = "120",
pages = "134--147",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - N′-((2-(6-bromo-2-oxo-2 H -chromen-3-yl)-1 H -indol-3-yl)methylene)benzohydrazide as a probable Bcl-2/Bcl-xL inhibitor with apoptotic and anti-metastatic potential

AU - Kamath, Pooja R.

AU - Sunil, Dhanya

AU - Ajees, A. Abdul

AU - Pai, K. S.R.

AU - Biswas, Shubankar

PY - 2016/9/14

Y1 - 2016/9/14

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84968816671&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84968816671&partnerID=8YFLogxK

U2 - 10.1021/ar0400995

DO - 10.1021/ar0400995

M3 - Article

C2 - 27187865

AN - SCOPUS:84968816671

VL - 120

SP - 134

EP - 147

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -