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

Članak u časopisu (Recenzirana verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
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.
Izvor:
Journal of Medicinal Chemistry, 2018, 61, 4, 1595-1608Izdavač:
- American Chemical Society (ACS)
Finansiranje / projekti:
- Sinteza aminohinolina i njihovih derivata kao antimalarika i inhibitora botulinum neurotoksina A (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]
Napomena:
- 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
Povezane informacije:
- Druga verzija
https://doi.org/10.1021/acs.jmedchem.7b01710 - Druga verzija
https://cer.ihtm.bg.ac.rs/handle/123456789/2325 - Povezani sadržaj
https://cer.ihtm.bg.ac.rs/handle/123456789/4515 - Povezani sadržaj
https://cer.ihtm.bg.ac.rs/handle/123456789/4516 - Povezani sadržaj
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
Institucija/grupa
IHTMTY - 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 . .