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Structure–Activity Relationships for Itraconazole-Based Triazolone Analogues as Hedgehog Pathway Inhibitors

  • Jennifer R. Pace
    Jennifer R. Pace
    Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, Connecticut 06269, United States
  • Kelly A. Teske
    Kelly A. Teske
    Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, Connecticut 06269, United States
  • Lianne Q. Chau
    Lianne Q. Chau
    Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States
  • Radha Charan Dash
    Radha Charan Dash
    Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, Connecticut 06269, United States
  • Angela M. Zaino
    Angela M. Zaino
    Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, Connecticut 06269, United States
  • Robert J. Wechsler-Reya
    Robert J. Wechsler-Reya
    Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States
  • , and 
  • M. Kyle Hadden*
    M. Kyle Hadden
    Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, Connecticut 06269, United States
    *E-mail: [email protected]. Tel: 1-860-486-8446. Fax: 1-860-486-6857.
Cite this: J. Med. Chem. 2019, 62, 8, 3873–3885
Publication Date (Web):March 21, 2019
https://doi.org/10.1021/acs.jmedchem.8b01283
Copyright © 2019 American Chemical Society

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    Abstract

    Abstract Image

    The Food and Drug Administration-approved antifungal agent, itraconazole (ITZ), has been increasingly studied for its novel biological properties. In particular, ITZ inhibits the hedgehog (Hh) signaling pathway and has the potential to serve as an anticancer chemotherapeutic against several Hh-dependent malignancies. We have extended our studies on ITZ analogues as Hh pathway inhibitors through the design, synthesis, and evaluation of novel des-triazole ITZ analogues that incorporate modifications to the triazolone/side chain region of the scaffold. Our overall results suggest that the triazolone/side chain region can be replaced with various functionalities (hydrazine carboxamides and meta-substituted amides) resulting in improved potency when compared to ITZ. Our studies also indicate that the stereochemical orientation of the dioxolane ring is important for both potent Hh pathway inhibition and compound stability. Finally, our studies suggest that the ITZ scaffold can be successfully modified in terms of functionality and stereochemistry to further improve its anti-Hh potency and physicochemical properties.

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b01283.

    • Synthesis protocols and characterization of previously disclosed ITZ intermediates; general protocols for pharmacokinetic assays; 1H and 13C NMR spectra for all new intermediates and final des-ITZ analogues; antiproliferation data within ASZ cells for compounds 27, 30, 34, and 39 (PDF)

    • Compound structures and associated biological data for compounds 142 are available within the molecular formula strings (PDB) (CSV)

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 8 publications.

    1. Li Wang, Guang Li, Lei Yang, Haonan Qu, Jing Cheng, Mohammed Abdallah, Dalia A. Barakat, Haibing Li. Highly Improved Chiral-Selective Resolution in Pillar[5]arene-Functionalized Molecularly Imprinted Membranes. ACS Applied Polymer Materials 2022, 4 (9) , 6723-6730. https://doi.org/10.1021/acsapm.2c01100
    2. Jiachen Wen, Divya Chennamadhavuni, Shana R. Morel, M. Kyle Hadden. Truncated Itraconazole Analogues Exhibiting Potent Anti-Hedgehog Activity and Improved Drug-like Properties. ACS Medicinal Chemistry Letters 2019, 10 (9) , 1290-1295. https://doi.org/10.1021/acsmedchemlett.9b00188
    3. Chao Ma, Kang Hu, Irfan Ullah, Qing-Kang Zheng, Nan Zhang, Zhi-Gang Sun. Molecular Mechanisms Involving the Sonic Hedgehog Pathway in Lung Cancer Therapy: Recent Advances. Frontiers in Oncology 2022, 12 https://doi.org/10.3389/fonc.2022.729088
    4. Jiachen Wen, M. Kyle Hadden. Medulloblastoma drugs in development: Current leads, trials and drawbacks. European Journal of Medicinal Chemistry 2021, 215 , 113268. https://doi.org/10.1016/j.ejmech.2021.113268
    5. Jennifer R. Pace, Rajan Jog, Diane J. Burgess, M. Kyle Hadden. Formulation and evaluation of itraconazole liposomes for Hedgehog pathway inhibition. Journal of Liposome Research 2020, 30 (3) , 305-311. https://doi.org/10.1080/08982104.2019.1668011
    6. Deborah Quaglio, Paola Infante, Lucia Di Marcotullio, Bruno Botta, Mattia Mori. Hedgehog signaling pathway inhibitors: an updated patent review (2015–present). Expert Opinion on Therapeutic Patents 2020, 30 (4) , 235-250. https://doi.org/10.1080/13543776.2020.1730327
    7. Jiachen Wen, Kelly A. Teske, M. Kyle Hadden. Inhibition of hedgehog signaling by stereochemically defined des-triazole itraconazole analogues. Bioorganic & Medicinal Chemistry Letters 2020, 30 (2) , 126794. https://doi.org/10.1016/j.bmcl.2019.126794
    8. Shulin Jiao, YaoJia Li, Zhiguo Gao, Ruicheng Chen, Yan Wang, Zhihong Zou. The synthesis of an antifungal 1,2,4-triazole drug and the establishment of a drug delivery system based on zeolitic imidazolate frameworks. New Journal of Chemistry 2019, 43 (47) , 18823-18831. https://doi.org/10.1039/C9NJ04432A

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