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Dizajn i sinteza inhibitora botulinum neurotoksina A i parazita Plasmodium falciparum

benzothiophene and steroidal derivatives of aminoquinoline

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2018
2766-teza.pdf (7.998Mb)
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Authors
Konstantinović, Jelena M.
Contributors
Šolaja, Bogdan A.
Milić, Dragana
Opsenica, Igor
Đurković-Đaković
Kostić, Vladimir S.
Doctoral thesis (Published version)
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Abstract
Botulinum neurotoksini su najjaĉi poznati prirodni otrovi i izazivaĉi botulizma –potencijalno smrtonosne neuroparalitiĉke bolesti. U poslednje vreme, sve veći brojstudija je usmeren ka pronalaţenju inhibitora botulinum neurotoksina serotipa A(BoNT/A) aktivnih unutar ćelije, jer terapija antitelima ima uspeha jedino pre nego štotoksin uĊe u neuron. U okviru ove doktorske disertacije izvršena je sinteza i detaljnoispitivanje inhibitorne aktivnosti novih steroidnih i benzo[b]tiofenskih derivata4-aminohinolina prema kratkom nizu (BoNT/A LC) i holotoksinu BoNT/A. Uistraţivanju je korišćen proteolitiĉki in vitro esej i ćelijski esej u motornim neuronimarazvijenim iz embrionalnih matiĉnih ćelija miša (mES-MN). Dodatno, molekulskomodelovanje i uklapanje novih derivata u aktivno mesto enzima izvršeno je korišćenjemprograma Schr dinger Suite 2016-4.U in vitro proteolitiĉkom eseju, sintetisana jedinjenja su ostvarila do 85%inhibicije BoNT/A LC pri koncentraciji 20 μM, dok su IC50 vrednosti bile u... opsegu 0,7–10,2 μM. U preintoksikacionom modelu u motornim neuronima razvijenim izembrionalnih matiĉnih ćelija miša (mES-MN) novi derivati su vršili zaštitu proteinaSNAP-25i do 88%, u niskim mikromolarnim koncentracijama i u dozno-zavisnomreţimu. Najaktivniji derivati su testirani u postintoksikacionom modelu, u kome sejedinjenja dodaju ćelijskoj kulturi 30 ili 60 minuta posle holotoksina. U oba modela jeuoĉena korelacija procenta zaštite SNAP-25 i primenjene koncentracije jedinjenja.Jedinjenje 17 (JK141) je pokazalo 99% zaštite SNAP-25 kada se administrira 30 minutaposle BoNT/A...

Botulinum neurotoxins are the most poisonous (biological) substances knownand causative agents of botulism – serious and potentially fatal neuroparalytic illness.Recently, the majority of efforts have focused on identification of botulinum neurotoxinserotype A (BoNT/A) inhibitors with intracellular activity, because antibody-basedtreatments are successful only before toxin enters a neuron. In this doctoral dissertationsynthesis and detailed evaluation of inhibitory potencies of new steroidal andbenzo[b]thiophene 4-aminoquinoline derivatives against BoNT/A light chain (LC) andfull length BoNT/A is reported. Both in vitro proteolytic assay and cell-based assayusing mouse embryonic stem cell derived motor neurons (mES-MNs) were employed.To rationalize the inhibitory potencies of the new derivatives, structure-based dockingsimulations were performed using Schr dinger Suite 2016-4 and the modules therein.Using in vitro HPLC-based assay, the newly synthesized molecules have shownBoNT/A LC in...hibition up to 85% at 20 μM and IC50 values ranging from 0.7–10.2 μM.Compounds tested during BoNT/A challenge in mES-MNs in preintoxication modelwere found to protect SNAP-25 proteinii by up to 88% at low μM concentrations and indose-dependent manner. The most effective derivatives were also tested in a postexposuremodel, where compounds were added 30 or 60 minutes following holotoxinadministration. In both pre- and postintoxication models, dose-dependent behavior wasobserved. Compound 17 (JK141) showed 99% of SNAP-25 cleavage protection whenadministrated 30 minutes after BoNT/A...

Keywords:
botulinum neurotoxin / small molecule inhibitors / aminoquinoline / steroid / antimalarials / Plasmodium falciparum / pharmacokinetics / benzotiophene / botulinum neurotoksin / mali molekuli kao inhibitori / aminohinolin / benzotiofen / antimalarici / Plasmodium falciparum / farmakokinetika / steroid
Source:
Универзитет у Београду, 2018
Publisher:
  • Универзитет у Београду, Хемијски факултет
Funding / projects:
  • The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors (RS-172008)
[ Google Scholar ]
Handle
https://hdl.handle.net/21.15107/rcub_nardus_9791
URI
http://eteze.bg.ac.rs/application/showtheses?thesesId=5940
https://fedorabg.bg.ac.rs/fedora/get/o:18090/bdef:Content/download
http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=50361871
http://nardus.mpn.gov.rs/123456789/9791
https://cherry.chem.bg.ac.rs/handle/123456789/2766
Collections
  • Doktorati
Institution/Community
Hemijski fakultet
TY  - THES
AU  - Konstantinović, Jelena M.
PY  - 2018
UR  - http://eteze.bg.ac.rs/application/showtheses?thesesId=5940
UR  - https://fedorabg.bg.ac.rs/fedora/get/o:18090/bdef:Content/download
UR  - http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=50361871
UR  - http://nardus.mpn.gov.rs/123456789/9791
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/2766
AB  - Botulinum neurotoksini su najjaĉi poznati prirodni otrovi i izazivaĉi botulizma –potencijalno smrtonosne neuroparalitiĉke bolesti. U poslednje vreme, sve veći brojstudija je usmeren ka pronalaţenju inhibitora botulinum neurotoksina serotipa A(BoNT/A) aktivnih unutar ćelije, jer terapija antitelima ima uspeha jedino pre nego štotoksin uĊe u neuron. U okviru ove doktorske disertacije izvršena je sinteza i detaljnoispitivanje inhibitorne aktivnosti novih steroidnih i benzo[b]tiofenskih derivata4-aminohinolina prema kratkom nizu (BoNT/A LC) i holotoksinu BoNT/A. Uistraţivanju je korišćen proteolitiĉki in vitro esej i ćelijski esej u motornim neuronimarazvijenim iz embrionalnih matiĉnih ćelija miša (mES-MN). Dodatno, molekulskomodelovanje i uklapanje novih derivata u aktivno mesto enzima izvršeno je korišćenjemprograma Schr dinger Suite 2016-4.U in vitro proteolitiĉkom eseju, sintetisana jedinjenja su ostvarila do 85%inhibicije BoNT/A LC pri koncentraciji 20 μM, dok su IC50 vrednosti bile u opsegu 0,7–10,2 μM. U preintoksikacionom modelu u motornim neuronima razvijenim izembrionalnih matiĉnih ćelija miša (mES-MN) novi derivati su vršili zaštitu proteinaSNAP-25i do 88%, u niskim mikromolarnim koncentracijama i u dozno-zavisnomreţimu. Najaktivniji derivati su testirani u postintoksikacionom modelu, u kome sejedinjenja dodaju ćelijskoj kulturi 30 ili 60 minuta posle holotoksina. U oba modela jeuoĉena korelacija procenta zaštite SNAP-25 i primenjene koncentracije jedinjenja.Jedinjenje 17 (JK141) je pokazalo 99% zaštite SNAP-25 kada se administrira 30 minutaposle BoNT/A...
AB  - Botulinum neurotoxins are the most poisonous (biological) substances knownand causative agents of botulism – serious and potentially fatal neuroparalytic illness.Recently, the majority of efforts have focused on identification of botulinum neurotoxinserotype A (BoNT/A) inhibitors with intracellular activity, because antibody-basedtreatments are successful only before toxin enters a neuron. In this doctoral dissertationsynthesis and detailed evaluation of inhibitory potencies of new steroidal andbenzo[b]thiophene 4-aminoquinoline derivatives against BoNT/A light chain (LC) andfull length BoNT/A is reported. Both in vitro proteolytic assay and cell-based assayusing mouse embryonic stem cell derived motor neurons (mES-MNs) were employed.To rationalize the inhibitory potencies of the new derivatives, structure-based dockingsimulations were performed using Schr dinger Suite 2016-4 and the modules therein.Using in vitro HPLC-based assay, the newly synthesized molecules have shownBoNT/A LC inhibition up to 85% at 20 μM and IC50 values ranging from 0.7–10.2 μM.Compounds tested during BoNT/A challenge in mES-MNs in preintoxication modelwere found to protect SNAP-25 proteinii by up to 88% at low μM concentrations and indose-dependent manner. The most effective derivatives were also tested in a postexposuremodel, where compounds were added 30 or 60 minutes following holotoxinadministration. In both pre- and postintoxication models, dose-dependent behavior wasobserved. Compound 17 (JK141) showed 99% of SNAP-25 cleavage protection whenadministrated 30 minutes after BoNT/A...
PB  - Универзитет у Београду, Хемијски факултет
T2  - Универзитет у Београду
T1  - Dizajn i sinteza inhibitora botulinum neurotoksina A i parazita Plasmodium falciparum
UR  - https://hdl.handle.net/21.15107/rcub_nardus_9791
ER  - 
@phdthesis{
author = "Konstantinović, Jelena M.",
year = "2018",
abstract = "Botulinum neurotoksini su najjaĉi poznati prirodni otrovi i izazivaĉi botulizma –potencijalno smrtonosne neuroparalitiĉke bolesti. U poslednje vreme, sve veći brojstudija je usmeren ka pronalaţenju inhibitora botulinum neurotoksina serotipa A(BoNT/A) aktivnih unutar ćelije, jer terapija antitelima ima uspeha jedino pre nego štotoksin uĊe u neuron. U okviru ove doktorske disertacije izvršena je sinteza i detaljnoispitivanje inhibitorne aktivnosti novih steroidnih i benzo[b]tiofenskih derivata4-aminohinolina prema kratkom nizu (BoNT/A LC) i holotoksinu BoNT/A. Uistraţivanju je korišćen proteolitiĉki in vitro esej i ćelijski esej u motornim neuronimarazvijenim iz embrionalnih matiĉnih ćelija miša (mES-MN). Dodatno, molekulskomodelovanje i uklapanje novih derivata u aktivno mesto enzima izvršeno je korišćenjemprograma Schr dinger Suite 2016-4.U in vitro proteolitiĉkom eseju, sintetisana jedinjenja su ostvarila do 85%inhibicije BoNT/A LC pri koncentraciji 20 μM, dok su IC50 vrednosti bile u opsegu 0,7–10,2 μM. U preintoksikacionom modelu u motornim neuronima razvijenim izembrionalnih matiĉnih ćelija miša (mES-MN) novi derivati su vršili zaštitu proteinaSNAP-25i do 88%, u niskim mikromolarnim koncentracijama i u dozno-zavisnomreţimu. Najaktivniji derivati su testirani u postintoksikacionom modelu, u kome sejedinjenja dodaju ćelijskoj kulturi 30 ili 60 minuta posle holotoksina. U oba modela jeuoĉena korelacija procenta zaštite SNAP-25 i primenjene koncentracije jedinjenja.Jedinjenje 17 (JK141) je pokazalo 99% zaštite SNAP-25 kada se administrira 30 minutaposle BoNT/A..., Botulinum neurotoxins are the most poisonous (biological) substances knownand causative agents of botulism – serious and potentially fatal neuroparalytic illness.Recently, the majority of efforts have focused on identification of botulinum neurotoxinserotype A (BoNT/A) inhibitors with intracellular activity, because antibody-basedtreatments are successful only before toxin enters a neuron. In this doctoral dissertationsynthesis and detailed evaluation of inhibitory potencies of new steroidal andbenzo[b]thiophene 4-aminoquinoline derivatives against BoNT/A light chain (LC) andfull length BoNT/A is reported. Both in vitro proteolytic assay and cell-based assayusing mouse embryonic stem cell derived motor neurons (mES-MNs) were employed.To rationalize the inhibitory potencies of the new derivatives, structure-based dockingsimulations were performed using Schr dinger Suite 2016-4 and the modules therein.Using in vitro HPLC-based assay, the newly synthesized molecules have shownBoNT/A LC inhibition up to 85% at 20 μM and IC50 values ranging from 0.7–10.2 μM.Compounds tested during BoNT/A challenge in mES-MNs in preintoxication modelwere found to protect SNAP-25 proteinii by up to 88% at low μM concentrations and indose-dependent manner. The most effective derivatives were also tested in a postexposuremodel, where compounds were added 30 or 60 minutes following holotoxinadministration. In both pre- and postintoxication models, dose-dependent behavior wasobserved. Compound 17 (JK141) showed 99% of SNAP-25 cleavage protection whenadministrated 30 minutes after BoNT/A...",
publisher = "Универзитет у Београду, Хемијски факултет",
journal = "Универзитет у Београду",
title = "Dizajn i sinteza inhibitora botulinum neurotoksina A i parazita Plasmodium falciparum",
url = "https://hdl.handle.net/21.15107/rcub_nardus_9791"
}
Konstantinović, J. M.. (2018). Dizajn i sinteza inhibitora botulinum neurotoksina A i parazita Plasmodium falciparum. in Универзитет у Београду
Универзитет у Београду, Хемијски факултет..
https://hdl.handle.net/21.15107/rcub_nardus_9791
Konstantinović JM. Dizajn i sinteza inhibitora botulinum neurotoksina A i parazita Plasmodium falciparum. in Универзитет у Београду. 2018;.
https://hdl.handle.net/21.15107/rcub_nardus_9791 .
Konstantinović, Jelena M., "Dizajn i sinteza inhibitora botulinum neurotoksina A i parazita Plasmodium falciparum" in Универзитет у Београду (2018),
https://hdl.handle.net/21.15107/rcub_nardus_9791 .

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