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Noscapinoids with anti-cancer activity against human acute lymphoblastic leukemia cells (CEM): a three dimensional chemical space pharmacophore modeling and electronic feature analysis

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Abstract

We have identified a new class of microtubule-binding compounds—noscapinoids—that alter microtubule dynamics at stoichiometric concentrations without affecting tubulin polymer mass. Noscapinoids show great promise as chemotherapeutic agents for the treatment of human cancers. To investigate the structural determinants of noscapinoids responsible for anti-cancer activity, we tested 36 structurally diverse noscapinoids in human acute lymphoblastic leukemia cells (CEM). The IC50 values of these noscapinoids vary from 1.2 to 56.0 μM. Pharmacophore models of anti-cancer activity were generated that identify two hydrogen bond acceptors, two aromatic rings, two hydrophobic groups, and one positively charged group as essential structural features. Additionally, an atom-based quantitative structure–activity relationship (QSAR) model was developed that gave a statistically satisfying result (R 2 = 0.912, Q 2 = 0.908, Pearson R = 0.951) and effectively predicts the anti-cancer activity of training and test set compounds. The pharmacophore model presented here is well supported by electronic property analysis using density functional theory at B3LYP/3-21*G level. Molecular electrostatic potential, particularly localization of negative potential near oxygen atoms of the dimethoxy isobenzofuranone ring of active compounds, matched the hydrogen bond acceptor feature of the generated pharmacophore. Our results further reveal that all active compounds have smaller lowest unoccupied molecular orbital (LUMO) energies concentrated over the dimethoxy isobenzofuranone ring, azido group, and nitro group, which is indicative of the electron acceptor capacity of the compounds. Results obtained from this study will be useful in the efficient design and development of more active noscapinoids.

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Acknowledgments

We thank Dr. William Beck for providing the drug-resistant CEM cell line used in this study and for advice. We are indebted to the anonymous reviewers of this manuscript for helpful suggestions. Grant support: National Institutes of Health (National Institute of Cancer) grants CA-095317-01A2 (H.C.J.) and Better Opportunities for Young Scientists in Chosen Areas of Science and Technology fellowship (SR/BY/L-37/09; Department of Science and Technology, Government of India) to P.K.N.

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Authors and Affiliations

  1. Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA

    Pradeep K. Naik & Harish C. Joshi

  2. Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan, 173215, Himachal Pradesh, India

    Seneha Santoshi

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  1. Pradeep K. Naik
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  2. Seneha Santoshi
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  3. Harish C. Joshi
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Correspondence to Pradeep K. Naik or Harish C. Joshi.

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Naik, P.K., Santoshi, S. & Joshi, H.C. Noscapinoids with anti-cancer activity against human acute lymphoblastic leukemia cells (CEM): a three dimensional chemical space pharmacophore modeling and electronic feature analysis. J Mol Model 18, 307–318 (2012). https://doi.org/10.1007/s00894-011-1057-9

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