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

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2018
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Authors
Konstantinović, Jelena M.
Kiris, Erkan
Kota, Krishna P.
Kugelman-Tonos, Johanny
Videnović, Milica
Cazares, Lisa H.
Terzić-Jovanović, Nataša
Verbić, Tatjana
Anđelković, Boban D.
Duplantier, Allen J.
Bavari, Sina
Šolaja, Bogdan
Article (Accepted Version)
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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.
Source:
Journal of Medicinal Chemistry, 2018, 61, 4, 1595-1608
Publisher:
  • American Chemical Society (ACS)
Funding / projects:
  • The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors (RS-172008)
  • U.S. Defense Threat Reduction Agency/Joint Science and Technology Office
  • Serbian Academy of Sciences and Arts
  • National Institute of Allergy and Infectious Diseases (U.S.) [5-U01AI082051-02, R33-AI101387]
Note:
  • The peer-reviewed version of the article: Konstantinović, J. M., Kiris, E., Kota, K. P., Kugelman-Tonos, J., Videnović, M., Cazares, L. H., Terzić-Jovanović, N., Verbić, T., Anđelković, B. D., Duplantier, A. J., Bavari, S.,& Šolaja, B. (2018). New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model. Journal of Medicinal Chemistry, American Chemical Society (ACS)., 61(4), 1595-1608.https://doi.org/10.1021/acs.jmedchem.7b01710
  • Published version: http://cer.ihtm.bg.ac.rs/handle/123456789/2325
  • Supporting information I: https://cer.ihtm.bg.ac.rs/handle/123456789/4515
  • Supporting information II: https://cer.ihtm.bg.ac.rs/handle/123456789/4516
  • Supporting information III: https://cer.ihtm.bg.ac.rs/handle/123456789/4517
Related info:
  • Version of
    https://doi.org/10.1021/acs.jmedchem.7b01710
  • Version of
    https://cer.ihtm.bg.ac.rs/handle/123456789/2325
  • Referenced by
    https://cer.ihtm.bg.ac.rs/handle/123456789/4515
  • Referenced by
    https://cer.ihtm.bg.ac.rs/handle/123456789/4516
  • Referenced by
    https://cer.ihtm.bg.ac.rs/handle/123456789/4517

DOI: 10.1021/acs.jmedchem.7b01710

ISSN: 0022-2623

PubMed: 29385334

WoS: 000426220900014

Scopus: 2-s2.0-85042675131
[ Google Scholar ]
6
4
URI
https://cer.ihtm.bg.ac.rs/handle/123456789/2935
Collections
  • Radovi istraživača / Researchers' publications
Institution/Community
IHTM
TY  - JOUR
AU  - Konstantinović, Jelena M.
AU  - Kiris, Erkan
AU  - Kota, Krishna P.
AU  - Kugelman-Tonos, Johanny
AU  - Videnović, Milica
AU  - Cazares, Lisa H.
AU  - Terzić-Jovanović, Nataša
AU  - Verbić, Tatjana
AU  - Anđelković, Boban D.
AU  - Duplantier, Allen J.
AU  - Bavari, Sina
AU  - Šolaja, Bogdan
PY  - 2018
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/2935
AB  - 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.
PB  - American Chemical Society (ACS)
T2  - Journal of Medicinal Chemistry
T1  - New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model
VL  - 61
IS  - 4
SP  - 1595
EP  - 1608
DO  - 10.1021/acs.jmedchem.7b01710
ER  - 
@article{
author = "Konstantinović, Jelena M. and Kiris, Erkan and Kota, Krishna P. and Kugelman-Tonos, Johanny and Videnović, Milica and Cazares, Lisa H. and Terzić-Jovanović, Nataša and Verbić, Tatjana and Anđelković, Boban D. and Duplantier, Allen J. and Bavari, Sina and Šolaja, Bogdan",
year = "2018",
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.",
publisher = "American Chemical Society (ACS)",
journal = "Journal of Medicinal Chemistry",
title = "New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model",
volume = "61",
number = "4",
pages = "1595-1608",
doi = "10.1021/acs.jmedchem.7b01710"
}
Konstantinović, J. M., Kiris, E., Kota, K. P., Kugelman-Tonos, J., Videnović, M., Cazares, L. H., Terzić-Jovanović, N., Verbić, T., Anđelković, B. D., Duplantier, A. J., Bavari, S.,& Šolaja, B.. (2018). New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model. in Journal of Medicinal Chemistry
American Chemical Society (ACS)., 61(4), 1595-1608.
https://doi.org/10.1021/acs.jmedchem.7b01710
Konstantinović JM, Kiris E, Kota KP, Kugelman-Tonos J, Videnović M, Cazares LH, Terzić-Jovanović N, Verbić T, Anđelković BD, Duplantier AJ, Bavari S, Šolaja B. New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model. in Journal of Medicinal Chemistry. 2018;61(4):1595-1608.
doi:10.1021/acs.jmedchem.7b01710 .
Konstantinović, Jelena M., Kiris, Erkan, Kota, Krishna P., Kugelman-Tonos, Johanny, Videnović, Milica, Cazares, Lisa H., Terzić-Jovanović, Nataša, Verbić, Tatjana, Anđelković, Boban D., Duplantier, Allen J., Bavari, Sina, Šolaja, Bogdan, "New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model" in Journal of Medicinal Chemistry, 61, no. 4 (2018):1595-1608,
https://doi.org/10.1021/acs.jmedchem.7b01710 . .

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