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Rational design of biaryl pharmacophore inserted noscapine derivatives as potent tubulin binding anticancer agents

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Abstract

We have strategically designed a series of noscapine derivatives by inserting biaryl pharmacophore (a major structural constituent of many of the microtubule-targeting natural anticancer compounds) onto the scaffold structure of noscapine. Molecular interaction of these derivatives with α,β-tubulin heterodimer was investigated by molecular docking, molecular dynamics simulation, and binding free energy calculation. The predictive binding affinity indicates that the newly designed noscapinoids bind to tubulin with a greater affinity. The predictive binding free energy (ΔGbind, pred) of these derivatives (ranging from −5.568 to −5.970 kcal/mol) based on linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model showed improved binding affinity with tubulin compared to the lead compound, natural α-noscapine (−5.505 kcal/mol). Guided by the computational findings, these new biaryl type α-noscapine congeners were synthesized from 9-bromo-α-noscapine using optimized Suzuki reaction conditions for further experimental evaluation. The derivatives showed improved inhibition of the proliferation of human breast cancer cells (MCF-7), human cervical cancer cells (HeLa) and human lung adenocarcinoma cells (A549), compared to natural noscapine. The cell cycle analysis in MCF-7 further revealed that these compounds alter the cell cycle profile and cause mitotic arrest at G2/M phase more strongly than noscapine. Tubulin binding assay revealed higher binding affinity to tubulin, as suggested by dissociation constant (Kd) of 126 ± 5.0 µM for 5a, 107 ± 5.0 µM for 5c, 70 ± 4.0 µM for 5d, and 68 ± 6.0 µM for 5e compared to noscapine (Kd of 152 ± 1.0 µM). In fact, the experimentally determined value of ΔGbind, expt (calculated from the Kd value) are consistent with the predicted value of ΔGbind, pred calculated based on LIE–SGB. Based on these results, one of the derivative 5e of this series was used for further toxicological evaluation. Treatment of mice with a daily dose of 300 mg/kg and a single dose of 600 mg/kg indicates that the compound does not induce detectable pathological abnormalities in normal tissues. Also there were no significant differences in hematological parameters between the treated and untreated groups. Hence, the newly designed noscapinoid, 5e is an orally bioavailable, safe and effective anticancer agent with a potential for the treatment of cancer and might be a candidate for clinical evaluation.

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Acknowledgments

We are thankful to Jaypee University of Information Technology, India, for providing student’s fellowship to Seneha Santoshi. We thank Mr. Birendra Patel, Professor in English, for proof reading the manuscript. We are greatly indebted to the anonymous reviewers of this manuscript for their helpful suggestions.

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Author notes

  1. Pradeep Kumar Naik

    Present address: Department of Biotechnology, Guru Ghasidas Vishwavidyalaya (A Central University), Koni, Bilaspur, 495 009, Chhattisgarh, India

Authors and Affiliations

  1. Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Distt. Solan, 173 234, Himachal Pradesh, India

    Seneha Santoshi, Charu Suri, Manya Sharma & Pradeep Kumar Naik

  2. Organic Chemistry Division-II (CPC Division), CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India

    Naresh Kumar Manchukonda & Srinivas Kantevari

  3. X-ray Crystallography Laboratory, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India

    Balasubramanian Sridhar

  4. Experimental Cancer Therapeutics and Chemical Biology, Department of Biology, UM-DAE Centre for Excellence in Basic Sciences, University of Mumbai, Kalina, Santa Cruz (E), Mumbai, 400 098, India

    Silja Joseph & Manu Lopus

  5. Department of Zoology, Guru Ghasidas Vishwavidyalaya (A Central University), Koni, Bilaspur, 495 009, Chhattisgarh, India

    Iswar Baitharu

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  1. Seneha Santoshi
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Santoshi, S., Manchukonda, N.K., Suri, C. et al. Rational design of biaryl pharmacophore inserted noscapine derivatives as potent tubulin binding anticancer agents. J Comput Aided Mol Des 29, 249–270 (2015). https://doi.org/10.1007/s10822-014-9820-5

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