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Discovery of noscapine derivatives as potential β-tubulin inhibitors.

Authors
  • Nemati, Faezeh1
  • Salehi, Peyman2
  • Bararjanian, Morteza1
  • Hadian, Nasim1
  • Mohebbi, Maryam1
  • Lauro, Gianluigi3
  • Ruggiero, Dafne3
  • Terracciano, Stefania3
  • Bifulco, Giuseppe3
  • Bruno, Ines4
  • 1 Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, G. C., Evin, 1983963113 Tehran, Iran. , (Iran)
  • 2 Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, G. C., Evin, 1983963113 Tehran, Iran. Electronic address: [email protected] , (Iran)
  • 3 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy. , (Italy)
  • 4 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy. Electronic address: [email protected] , (Italy)
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Aug 09, 2020
Volume
30
Issue
20
Pages
127489–127489
Identifiers
DOI: 10.1016/j.bmcl.2020.127489
PMID: 32784088
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Twenty novel 1,2,3-triazole noscapine derivatives were synthesized starting from noscapine by consecutive N-demethylation, reduction of lactone ring, N-propargylation and Huisgen 1,3-dipolar cycloaddition reaction. In order to select the most promising molecules to subject to further biophysical and biological evaluation, a molecular docking analysis round was performed using noscapine as reference compound. The molecules featuring docking predicted binding affinity better than that of noscapine were then subjected to MTT assay against MCF7 cell line. The obtained results disclosed that all the selected triazole derivatives exhibited a remarkably lower cell viability compared to noscapine in the range of 20 μM in 48 h. In an attempt to correlate the biological activity with the ability to bind tubulin, the surface plasmon resonance (SPR) assay was employed. Compounds 8a, 8h, 9c, 9f and 9j were able to bind tubulin with affinity constant values in the nanomolar range and higher if compared to noscapine. Integrating computational predictions and experimental evaluation, two promising compounds (8h and 9c) were identified, whose relevant cytotoxicity was supposed to be correlated with tubulin binding affinity. These findings shed lights onto structural modifications of noscapine toward the identification of more potent cytotoxic agents targeting tubulin. Copyright © 2020 Elsevier Ltd. All rights reserved.

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