Microwave-assisted synthesis, characterization and cytotoxic studies of novel estrogen receptor α ligands towards human breast cancer cells

Hanumantharayappa Bharathkumar; Chakrabhavi Dhananjaya Mohan; Hanumappa Ananda; Julian E Fuchs; Feng Li; Shobith Rangappa; Mohan Surender; Krishna C Bulusu; Kesturu S Girish; Gautam Sethi; Andreas Bender; Basappa; Kanchugarakoppal S Rangappa

doi:10.1016/j.bmcl.2015.01.030

Microwave-assisted synthesis, characterization and cytotoxic studies of novel estrogen receptor α ligands towards human breast cancer cells

Bioorg Med Chem Lett. 2015 Apr 15;25(8):1804-1807. doi: 10.1016/j.bmcl.2015.01.030. Epub 2015 Feb 7.

Affiliations

¹ Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Palace Road, Bangalore 560 001, India.
² Department of Chemistry, University of Mysore, Mysore 570 006, India.
³ Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, United Kingdom.
⁴ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117 597, Singapore.
⁵ Frontier Research Center for Post-genome Science and Technology Hokkaido University, Sapporo 060 0808, Japan.
⁶ CAS in Crystallography and Biophysics, University of Madras, Chennai 600 025, Tamil Nadu, India.
⁷ Department of Studies and Research in Biochemistry, Tumkur University, Tumkur 572 103, India.

PMID: 25797502
DOI: 10.1016/j.bmcl.2015.01.030

Abstract

A new, simple, and microwave-assisted, solution-phase T3P®-DMSO mediated method for the preparation of a novel class of estrogen receptor alpha (ERα) ligands based on the 2-phenylquinoline scaffold was developed. Furthermore, the novel ERα ligands were tested for their bioactivity against ERα-positive and ERα-negative cell lines. The ligand (entry 4), with amine and nitro group substitution at C4 position, displayed significant cytotoxicity against MCF-7 and HepG2 cells with an IC50 value of 6 and 11μM, respectively. On the other hand, ERα-negative cells displayed resistance to quinolines induced cytotoxicity with an IC50 value >100Mm and they does not induce cytotoxicity in normal breast epithelial cells. Molecular docking analyses suggest a consistent binding mode for these ERα ligands in the ligand binding domain of the human ERα and predict the ligands to occupy the hydrophobic cavity in a similar fashion as estradiol or GW2368.

Keywords: Cancer; Estrogen receptor ligand; Molecular docking; Quinolines; T3P-DMSO mediated synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Binding Sites
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Line, Tumor
Estrogen Receptor alpha / chemistry*
Estrogen Receptor alpha / metabolism
Female
Hep G2 Cells
Humans
Ligands*
MCF-7 Cells
Microwaves*
Molecular Docking Simulation
Protein Binding
Protein Structure, Tertiary
Quinolines / chemical synthesis
Quinolines / chemistry
Quinolines / pharmacology

Substances

Antineoplastic Agents
ESR1 protein, human
Estrogen Receptor alpha
Ligands
Quinolines
quinoline