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Dizajn i sinteza inhibitora botulinum neurotoksina A i parazita Plasmodium falciparum
benzothiophene and steroidal derivatives of aminoquinoline
dc.contributor.advisor | Šolaja, Bogdan A. | |
dc.contributor.other | Milić, Dragana | |
dc.contributor.other | Opsenica, Igor | |
dc.contributor.other | Đurković-Đaković | |
dc.contributor.other | Kostić, Vladimir S. | |
dc.creator | Konstantinović, Jelena M. | |
dc.date.accessioned | 2018-11-22T00:45:58Z | |
dc.date.available | 2018-11-22T00:45:58Z | |
dc.date.issued | 2018 | |
dc.identifier.uri | http://eteze.bg.ac.rs/application/showtheses?thesesId=5940 | |
dc.identifier.uri | https://fedorabg.bg.ac.rs/fedora/get/o:18090/bdef:Content/download | |
dc.identifier.uri | http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=50361871 | |
dc.identifier.uri | http://nardus.mpn.gov.rs/123456789/9791 | |
dc.identifier.uri | https://cherry.chem.bg.ac.rs/handle/123456789/2766 | |
dc.description.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... | sr |
dc.description.abstract | 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... | en |
dc.format | application/pdf | |
dc.language | sr | |
dc.publisher | Универзитет у Београду, Хемијски факултет | sr |
dc.relation | info:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172008/RS// | |
dc.rights | openAccess | en |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.source | Универзитет у Београду | sr |
dc.subject | botulinum neurotoxin | en |
dc.subject | small molecule inhibitors | en |
dc.subject | aminoquinoline | en |
dc.subject | steroid | en |
dc.subject | antimalarials | en |
dc.subject | Plasmodium falciparum | en |
dc.subject | pharmacokinetics | en |
dc.subject | benzotiophene | en |
dc.subject | botulinum neurotoksin | sr |
dc.subject | mali molekuli kao inhibitori | sr |
dc.subject | aminohinolin | sr |
dc.subject | benzotiofen | sr |
dc.subject | antimalarici | sr |
dc.subject | Plasmodium falciparum | sr |
dc.subject | farmakokinetika | sr |
dc.subject | steroid | sr |
dc.title | Dizajn i sinteza inhibitora botulinum neurotoksina A i parazita Plasmodium falciparum | sr |
dc.title.alternative | benzothiophene and steroidal derivatives of aminoquinoline | en |
dc.type | doctoralThesis | en |
dc.rights.license | BY-NC-ND | |
dc.rights.license | ARR | |
dcterms.abstract | Шолаја, Богдан A.; Милић, Драгана; Опсеница, Игор; Ђурковић-Ђаковић; Костић, Владимир С.; Константиновић, Јелена М.; Дизајн и синтеза инхибитора ботулинум неуротоксина A и паразита Пласмодиум фалципарум; Дизајн и синтеза инхибитора ботулинум неуротоксина A и паразита Пласмодиум фалципарум; | |
dc.type.version | publishedVersion | en |
dc.identifier.fulltext | https://cherry.chem.bg.ac.rs/bitstream/id/9651/2766.pdf | |
dc.identifier.fulltext | https://cherry.chem.bg.ac.rs/bitstream/id/14192/2766-teza.pdf | |
dc.identifier.rcub | https://hdl.handle.net/21.15107/rcub_nardus_9791 |