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New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model

  1. Author:
    Konstantinovic, Jelena
    Kiris, Erkan
    Kota, Krishna P.
    Kugelman-Tonos, Johanny
    Videnovic, Milica
    Cazares, Lisa H.
    Jovanovic, Natasa Terzic
    Verbic, Tatjana Z.
    Andjelkoyic, Boban
    Duplantier, Allen J.
    Bavari, Sina
    Solaja, Bogdan A.

  2. Author Address

    Univ Belgrade, Fac Chem, Studentski Trg 16,POB 51, Belgrade 11158, Serbia.NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA.US Army Med Res Inst Infect Dis, Mol & Translat Sci Div, 1425 Porter St, Frederick, MD 21702 USA.Fac Chem Innovat Ctr, Studentski Trg 12-16, Belgrade 11158, Serbia.Univ Belgrade, Inst Chem Technol & Met, Njegoseva 12, Belgrade 11000, Serbia.US Army Med Res Inst Infect Dis, 1425 Porter St, Frederick, MD 21702 USA.Serbian Acad Arts & Sci, Knez Mihailova 3, Belgrade 11158, Serbia.
    1. Year: 2018
    2. Date: Feb 22
  2. Journal: Journal of Medicinal Chemistry
  3. AMER CHEMICAL SOC,
    1. 61
    2. 4
    3. Pages: 1595-1608
  5. Type of Article: Article
  6. ISSN: 0022-2623
  1. Abstract:

    The synthesis and inhibitory potencies against botulinum neurotoxin serotype A light chain (BoNT/A LC) using in vitro HPLC based enzymatic assay for various steroidal, benzothiophene, thiophene, and adamantane 4-aminoquinoline derivatives are described. In addition, the compounds were evaluated for the activity against BoNT/A holotoxin in mouse embryonic stem cell derived motor neurons. Steroidal derivative 16 showed remarkable protection (up to 89% of uncleaved SNAP-25) even when administered 30 min postintoxication. This appears to be the first example of LC inhibitors antagonizing BoNT intoxication in mouse embryonic stem cell derived motor neurons (mES-MNs) in a postexposure model. Oral administration of 16 was well tolerated in the mouse up to 600 mg/kg, q.d. Although adequate unbound drug levels were not achieved at this dose, the favorable in vitro ADMET results strongly support further work in this series.

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External Sources

  1. View Full Text
  2. DOI: 10.1021/acs.jmedchem.7b01710
  3. PMID: 29385334
  4. PMCID: PMC5833296
  5. View record in Web of Science®
  6. WOS: 000426220900014

Library Notes

  1. Fiscal Year: FY2017-2018
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