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

Mohd Kamil Hussain, Deependra Kumar Singh, Akhilesh Singh, Mohd Asad, Mohd Imran Ansari, Mohammad Shameem, Shagun Krishna, Guru R. Valicherla, Vishal Makadia, Sanjeev Meena, Amit Laxmikant Deshmukh, Jiaur R. Gayen, Mohammad Imran Siddiqi, Dipak Datta, Kanchan Hajela, Dibyendu Banerjee

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8 Scopus citations

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.

Original languageEnglish (US)
Article number10715
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

Bibliographical note

Funding Information:
The authors acknowledge CSIR-CDRI, Govt. of India, for financial and infrastructural support. Financial support is also acknowledged from Department of Biotechnology (DBT), Govt. of India (Grant-BT/PR6421/ GBD/27/436/2012), the Department of Science and Technology (DST), Govt. of India (Grant-SB/FT/LS-163/2012) and CSIR Network projects GENESIS (BSC0121) and Biopros (BSC0106). The authors are also thankful to Sophisticated Analytical Instrument Facility (SAIF) CDRI, Lucknow, India, for providing spectral analysis data of chemical compounds and for support with cell based flow cytometry experiments. MKH and DKS are thankful for their Senior Research fellowships from Council of Scientific and Industrial Research (CSIR). The manuscript bears the CDRI communication number 9558.

Publisher Copyright:
© 2017 The Author(s).

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