A Novel Benzocoumarin-Stilbene Hybrid as a DNA ligase I inhibitor with in vitro and in vivo anti-tumor activity in breast cancer models

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 B...

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Bibliographic Details
Published in:Scientific reports 2017-09, Vol.7 (1), p.10715-14, Article 10715
Main Authors: Hussain, Mohd. Kamil, Singh, Deependra Kumar, Singh, Akhilesh, Asad, Mohd, Ansari, Mohd. Imran, Shameem, Mohammad, Krishna, Shagun, Valicherla, Guru R., Makadia, Vishal, Meena, Sanjeev, Deshmukh, Amit Laxmikant, Gayen, Jiaur R., Imran Siddiqi, Mohammad, Datta, Dipak, Hajela, Kanchan, Banerjee, Dibyendu
Format: Article
Language:English
Subjects:
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Animal models
Antitumor activity
Antitumor agents
Breast cancer
Deoxyribonucleic acid
DNA
DNA ligase (ATP)
Drug development
Drug resistance
Enzymatic activity
Humanities and Social Sciences
multidisciplinary
Science
Science (multidisciplinary)
Toxicity
Tumor cell lines
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-10864-3