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

Autor:	Hussain MK; Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, 226031, India.; Department of Chemistry Govt. Raza Post Graduate College, Rampur, 244901, India., Singh DK; Molecular and Structural Biology Division, CSIR-CDRI, Lucknow, 226031, India., Singh A; Biochemistry Division, CSIR-CDRI, Lucknow, 226031, India., Asad M; Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, 226031, India., Ansari MI; Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, 226031, India., Shameem M; Molecular and Structural Biology Division, CSIR-CDRI, Lucknow, 226031, India., Krishna S; Molecular and Structural Biology Division, CSIR-CDRI, Lucknow, 226031, India., Valicherla GR; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.; Pharmacokinetics and Metabolism Division, CSIR-CDRI, Lucknow, 226031, India., Makadia V; Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Raibarelly, India., Meena S; Biochemistry Division, CSIR-CDRI, Lucknow, 226031, India., Deshmukh AL; Molecular and Structural Biology Division, CSIR-CDRI, Lucknow, 226031, India., Gayen JR; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.; Pharmacokinetics and Metabolism Division, CSIR-CDRI, Lucknow, 226031, India., Imran Siddiqi M; Molecular and Structural Biology Division, CSIR-CDRI, Lucknow, 226031, India.; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India., Datta D; Biochemistry Division, CSIR-CDRI, Lucknow, 226031, India. dipak.datta@cdri.res.in.; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India. dipak.datta@cdri.res.in., Hajela K; Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, 226031, India. kanchan_hajela@cdri.res.in.; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India. kanchan_hajela@cdri.res.in., Banerjee D; Molecular and Structural Biology Division, CSIR-CDRI, Lucknow, 226031, India. d.banerjee@cdri.res.in.; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India. d.banerjee@cdri.res.in.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2017 Sep 06; Vol. 7 (1), pp. 10715. Date of Electronic Publication: 2017 Sep 06.
DOI:	10.1038/s41598-017-10864-3
Abstrakt:	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.
Databáze:	MEDLINE
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