ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
CONTENT TYPES

Figure 1Loading Img

Development of a Redox-Sensitive Spermine Prodrug for the Potential Treatment of Snyder Robinson Syndrome

  • Mukund P. Tantak
    Mukund P. Tantak
    Department of Medical Education, College of Medicine, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826-3227, United States
  • Vandana Sekhar
    Vandana Sekhar
    Department of Medical Education, College of Medicine, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826-3227, United States
  • Xianzun Tao
    Xianzun Tao
    Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, 1600 NW 10th Ave, Miami, Florida 33136, United States
    More by Xianzun Tao
  • R. Grace Zhai
    R. Grace Zhai
    Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, 1600 NW 10th Ave, Miami, Florida 33136, United States
  • , and 
  • Otto Phanstiel IV*
    Otto Phanstiel, IV
    Department of Medical Education, College of Medicine, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826-3227, United States
    *Email: [email protected].Tel.: 407-823-6545. Fax: 407-384-2062.
Cite this: J. Med. Chem. 2021, 64, 21, 15593–15607
Publication Date (Web):October 25, 2021
https://doi.org/10.1021/acs.jmedchem.1c00419
Copyright © 2021 American Chemical Society

    Article Views

    1612

    Altmetric

    -

    Citations

    LEARN ABOUT THESE METRICS
    Other access options
    Supporting Info (2)»

    Abstract

    Abstract Image

    Snyder Robinson Syndrome (SRS) is a rare disease associated with a defective spermine synthase gene and low intracellular spermine levels. In this study, a spermine replacement therapy was developed using a spermine prodrug that enters cells via the polyamine transport system. The prodrug was comprised of three components: a redox-sensitive quinone “trigger”, a “trimethyl lock (TML)” aryl “release mechanism”, and spermine. The presence of spermine in the design facilitated uptake by the polyamine transport system. The quinone–TML motifs provided a redox-sensitive agent, which upon intracellular reduction generated a hydroquinone, which underwent intramolecular cyclization to release free spermine and a lactone byproduct. Rewardingly, most SRS fibroblasts treated with the prodrug revealed a significant increase in intracellular spermine. Administering the spermine prodrug through feeding in a Drosophila model of SRS showed significant beneficial effects. In summary, a spermine prodrug is developed and provides a lead compound for future spermine replacement therapy experiments.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00419.

    • CV details and profile for prodrug 1, polyamine levels in CMS-23916 cells treated with prodrug 1 (at 50 μM or 5 μM), CDAP (100 μM), or Spm (5 μM), graph showing an increased intensity of Mitoview 633 staining (APC-A) in CMS-23916 cells pretreated for 6 h with NAC (N) (2 mM) followed by 24 h incubation period, polyamine levels in CMS-6233 (mutant) fibroblasts cultured for 24 h in the presence of aminoguanidine (1 mM) with or without treatment of prodrug 1 or Spm (5 μM) for 24 h, 1H NMR, 13C NMR, and high-resolution mass spectra of compounds 1 and 5–8, elemental analyses for compound 1, HPLC purity checks for compounds 6 and 8 (PDF)

    • Bioactivities observed (CSV)

    Terms & Conditions

    Electronic Supporting Information files are available without a subscription to ACS Web Editions. The American Chemical Society holds a copyright ownership interest in any copyrightable Supporting Information. Files available from the ACS website may be downloaded for personal use only. Users are not otherwise permitted to reproduce, republish, redistribute, or sell any Supporting Information from the ACS website, either in whole or in part, in either machine-readable form or any other form without permission from the American Chemical Society. For permission to reproduce, republish and redistribute this material, requesters must process their own requests via the RightsLink permission system. Information about how to use the RightsLink permission system can be found at http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 4 publications.

    1. Jin Zhang, Xiangchao Xu, Guoqiang Zhao, Heng You, Rongzhou Wang, Feng Li. Hydrogenation of Quinones to Hydroquinones under Atmospheric Pressure Catalyzed by a Metal–Ligand Bifunctional Iridium Catalyst. Organic Letters 2024, 26 (9) , 1857-1862. https://doi.org/10.1021/acs.orglett.4c00064
    2. Charles E. Schwartz, Raymond J. Louie, Annick Toutain, Cindy Skinner, Michael J. Friez, Roger E. Stevenson. X‐Linked intellectual disability update 2022. American Journal of Medical Genetics Part A 2023, 191 (1) , 144-159. https://doi.org/10.1002/ajmg.a.63008
    3. Zhenyun Guo, Xiang Zhang, Chengjie Lin, Yue Huang, Yun Zhong, Hailing Guo, Zhou Zheng, Shangeng Weng. METTL3-IGF2BP3-axis mediates the proliferation and migration of pancreatic cancer by regulating spermine synthase m6A modification. Frontiers in Oncology 2022, 12 https://doi.org/10.3389/fonc.2022.962204
    4. Xianzun Tao, Yi Zhu, Zoraida Diaz-Perez, Seok-Ho Yu, Jackson R. Foley, Tracy Murray Stewart, Robert A. Casero, Richard Steet, R. Grace Zhai. Phenylbutyrate modulates polyamine acetylase and ameliorates Snyder-Robinson syndrome in a Drosophila model and patient cells. JCI Insight 2022, 7 (13) https://doi.org/10.1172/jci.insight.158457

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    MENDELEY PAIRING EXPIRED
    Your Mendeley pairing has expired. Please reconnect