Abstract
Existing cancer therapies are often associated with drug resistance and toxicity, which results in poor prognosis and recurrence of cancer. This necessitates the identification and development of novel therapeutics against existing as well as novel cellular targets. In this study, a novel class of Benzocoumarin-Stilbene hybrid molecules were synthesized and evaluated for their antiproliferative activity against various cancer cell lines followed by in vivo antitumor activity in a mouse model of cancer. The most promising molecule among the series, i.e. compound (E)-4-(3,5-dimethoxystyryl)-2H-benzo[h]chromen-2-one (19) showed maximum antiproliferative activity in breast cancer cell lines (MDA-MB-231 and 4T1) and decreased the tumor size in the in-vivo 4T1 cell-induced orthotopic syngeneic mouse breast cancer model. The mechanistic studies of compound 19 by various biochemical, cell biology and biophysical approaches suggest that the compound binds to and inhibits the human DNA ligase I enzyme activity that might be the cause for significant reduction in tumor growth and may constitute a promising next-generation therapy against breast cancers.
Highlights
Molecular hybridization is an important strategy in drug design and development based on the combination of pharmacophoric moieties of different bioactive molecules to produce a new hybrid compound with improved medicinal properties as compared to the parent molecules
At 10 μM concentration, compounds 16, 19 and 26 showed significant activity ( > 50% inhibition) in MDA-MB-231 cells (Supplementary Table 1). The activity of these compounds were further checked in different cancer cell lines such as Colorectal adenocarcinoma (DLD-1), Liver hepatoma (PLC/PRF/5), Lung carcinoma (A549), Ovarian adenocarcinoma (SK-OV-3), Brain glioblastoma (A-172), Pancreatic adenocarcinoma (PANC-1), and triple negative mouse breast cancer cell line (4T1) (Supplementary Table 2)
A novel class of compounds belonging to the Benzocoumarin-Stilbene hybrid family have been synthesized with the help of molecular hybridization approach
Summary
Molecular hybridization is an important strategy in drug design and development based on the combination of pharmacophoric moieties of different bioactive molecules to produce a new hybrid compound with improved medicinal properties as compared to the parent molecules. Out of 30 compounds one compound i.e. compound 19 showed better antiproliferative activity against the tested cancer cell lines as compared to their parent compounds (Neo-tanshinlactone and Resveratrol). Our in-silico studies showed that compound 19 may preferentially interact with human DNA ligase I (hLigI) protein, among various replication proteins that were tested. Human DNA ligases are important proteins that maintain the genomic integrity of cells by joining the DNA strand breaks during DNA replication and repair processes[4,5,6,7,8]. An inhibition of hLigI activity leads to deficiency of DNA joining during DNA replication and repair process that leads to accumulation of DNA strand breaks leading to cell death[7, 9]. For the first time, we demonstrate an in-vivo active hLigI inhibitor which could be a lead molecule for the development of successful drug candidates
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