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Chem-bioinformatics and in vitro approaches for candidate optimization: a case study of NSC745689 as a promising antitumor agent

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Abstract

The benzothiazole scaffold has been reported to have antitumor activity in tumor-sensitive cell lines by proposed mechanism of CYP1A1 induction. CYP1A1 has been shown to participate in metabolism of benzothiazole scaffold to its reactive metabolites. CYP1A1 has also been proposed as drug target for anti-cancer chemotherapy for its differential and selective overexpression in tumor cells. Herein, we have reported NSC745689 from the series of new pyrimidobenzothiazoles (NSC745689) for its promising antitumor activity against non-small cell lung cancer cell line in National Cancer Institute (NCI) 60 human cancer cell line screen. We confirmed CYP1A1 specificity for NSC745689 by ethoxyresorufin-O-dethylase (EROD) assay. Furthermore, we investigated the metabolism of NSC745689 using MetaSite software and quantum mechanical study. The necessary structural changes in NSC745689 scaffold to potentiate its CYP1A1 binding and antitumor activity were suggested using molecular docking and molecular dynamics analysis.

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Acknowledgments

The authors acknowledge financial support from Department of Biotechnology (DBT), New Delhi.

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The authors have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Mohali, 160062, Punjab, India

    Prajwal P. Nandekar, Khaled M. Tumbi, Nitu Bansal, Vijay P. Rathod & Abhay T. Sangamwar

  2. Department of Pharmaceutical Chemistry, Nanded Pharmacy College, Nanded, 431602, Maharashtra, India

    Leena B. Labhsetwar

  3. Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Mohali, 160062, Punjab, India

    Neelagiri Soumya & Sushma Singh

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  1. Prajwal P. Nandekar
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  2. Khaled M. Tumbi
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  4. Vijay P. Rathod
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  5. Leena B. Labhsetwar
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  6. Neelagiri Soumya
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  7. Sushma Singh
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  8. Abhay T. Sangamwar
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Correspondence to Abhay T. Sangamwar.

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Nandekar, P.P., Tumbi, K.M., Bansal, N. et al. Chem-bioinformatics and in vitro approaches for candidate optimization: a case study of NSC745689 as a promising antitumor agent. Med Chem Res 22, 3728–3742 (2013). https://doi.org/10.1007/s00044-012-0364-8

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