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    Development of 1,8-Naphthalimides as Clathrin Inhibitors
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    † Chemistry, Centre for Chemical Biology, The University of Newcastle, University Drive, Callaghan, New South Wales 2308 Australia
    ‡ Leibniz Institut für Molekulare Pharmakologie and Freie Universität Berlin, 13125 Berlin, Germany
    § Cell Signaling Unit, Children’s Medical Research Institute, The University of Sydney, Sydney, New South Wales 2145, Australia
    *Phone: + 612 4921-6486; fax: +612 4921-5472; e-mail: [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2014, 57, 1, 131–143
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    https://doi.org/10.1021/jm4015263
    Published December 3, 2013
    Copyright © 2013 American Chemical Society
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    Abstract

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    We reported the first small molecule inhibitors of the interaction between the clathrin N-terminal domain (TD) and endocyctic accessory proteins (i.e., clathrin inhibition1). Initial screening of a ∼17 000 small molecule ChemBioNet library identified 1. Screening of an existing in-house propriety library identified four substituted 1,8-napthalimides as ∼80–120 μM clathrin inhibitors. Focused library development gave 3-sulfo-N-(4-aminobenzyl)-1,8-naphthalimide, potassium salt (18, IC50 ≈ 18 μM). A second library targeting the 4-aminobenzyl moiety was developed, and four analogues displayed comparable activity (26, 27, 28, 34 with IC50 values of 22, 16, 15, and 15 μM respectively) with a further four (24, 25, 32, 33) more active than 18 with IC50 values of 10, 6.9, 12, and 10 μM, respectively. Docking studies rationalized the structure–activity relationship (SAR) with the biological data. 3-Sulfo-N-benzyl-1,8-naphthalimide, potassium salt (25) with an IC50 ≈ 6.9 μM, is the most potent clathrin terminal domain–amphiphysin inhibitor reported to date.

    Copyright © 2013 American Chemical Society

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    Supporting Information

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    1H and 13CNMR spectra for compounds 10a, 16a, 2a, 17a, 21, 2–19, and 22–34; and HRMS data for compounds 2–7, 9, 12–19, and 22–34. This material is available free of charge via the Internet at http://pubs.acs.org.

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    This article is cited by 24 publications.

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    11. Bahta Muzey, Ahmed Naseem. An AIEE active 1, 8-naphthalimide- sulfamethizole probe for ratiometric fluorescent detection of Hg2+ ions in aqueous media. Journal of Photochemistry and Photobiology A: Chemistry 2020, 391 , 112354. https://doi.org/10.1016/j.jphotochem.2020.112354
    12. Muzey Bahta, Naseem Ahmed. Naphthalimide-amino acid conjugates chemosensors for Hg2+ detection: Based on chelation mediated emission enhancement in aqueous solution. Journal of Photochemistry and Photobiology A: Chemistry 2019, 378 , 85-93. https://doi.org/10.1016/j.jphotochem.2019.04.027
    13. Muzey Bahta, Naseem Ahmed. A novel 1,8-naphthalimide as highly selective naked-eye and ratiometric fluorescent sensor for detection of Hg2+ ions. Journal of Photochemistry and Photobiology A: Chemistry 2019, 373 , 154-161. https://doi.org/10.1016/j.jphotochem.2019.01.009
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    17. Mahaveer Singh, Hemant R. Jadhav, Tanya Bhatt. Dynamin Functions and Ligands: Classical Mechanisms Behind. Molecular Pharmacology 2017, 91 (2) , 123-134. https://doi.org/10.1124/mol.116.105064
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    19. Pattan Sirajuddin Nayab, Madhusudana Pulaganti, Suresh Kumar Chitta, Mohammad Abid, Rahis Uddin. Evaluation of DNA Binding, Radicals Scavenging and Antimicrobial Studies of Newly Synthesized N-Substituted Naphthalimides: Spectroscopic and Molecular Docking Investigations. Journal of Fluorescence 2015, 25 (6) , 1905-1920. https://doi.org/10.1007/s10895-015-1683-1
    20. Callista B. Harper, Adam McCluskey, Phillip J. Robinson, Frederic A. Meunier. Exploiting endocytic pathways to prevent bacterial toxin infection. 2015, 1072-1094. https://doi.org/10.1016/B978-0-12-800188-2.00037-9
    21. Mohammed K. Abdel-Hamid, Kylie A. Macgregor, Luke R. Odell, Ngoc Chau, Anna Mariana, Ainslie Whiting, Phillip J. Robinson, Adam McCluskey. 1,8-Naphthalimide derivatives: new leads against dynamin I GTPase activity. Organic & Biomolecular Chemistry 2015, 13 (29) , 8016-8028. https://doi.org/10.1039/C5OB00751H
    22. Mark J Robertson, Fiona M Deane, Wiebke Stahlschmidt, Lisa von Kleist, Volker Haucke, Phillip J Robinson, Adam McCluskey. Synthesis of the Pitstop family of clathrin inhibitors. Nature Protocols 2014, 9 (7) , 1592-1606. https://doi.org/10.1038/nprot.2014.106
    23. Anna K. Willox, Yasmina M. E. Sahraoui, Stephen J. Royle. Non-specificity of Pitstop 2 in clathrin-mediated endocytosis. Biology Open 2014, 3 (5) , 326-331. https://doi.org/10.1242/bio.20147955
    24. Mohammed Abdel-Hamid, Adam McCluskey. In Silico Docking, Molecular Dynamics and Binding Energy Insights into the Bolinaquinone-Clathrin Terminal Domain Binding Site. Molecules 2014, 19 (5) , 6609-6622. https://doi.org/10.3390/molecules19056609
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2014, 57, 1, 131–143
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm4015263
    Published December 3, 2013
    Copyright © 2013 American Chemical Society
    Request reuse permissions

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