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Sinteza in biokemijsko vrednotenje nepeptidnih reverzibilnih in ireverzibilnih zaviralcev imunoproteasoma = Synthesis and biochemical evaluation of nonpeptidic reversible and irreversible immunoproteasome inhibitors : doktorska disertacijaShannon Schiffrer, EvaEvkariontski proteasom je središče ubikvitin-proteasomskega sistema, ki je odgovoren za ohranjanje homeostaze proteinov ter regulacijo celičnih procesov. Ločimo dve glavni obliki, in sicer ... konstitutivni proteasom, ki se izraža v vseh evkariontskih celicah, ter imunoproteasom, ki se izraža v hematopoetskih celicah ter v vseh evkariontskih celicah med akutnimi imunskimi in stresnimi odgovori. Zaviralci obeh oblik proteasoma so perspektivne učinkovine za zdravljenje različnih bolezni, vključujoč nevrodegenerativne bolezni. Napredek v poznavanju imunoproteasoma ter njegove vloge pri različnih boleznih v zadnjih letih je vodil do napredka v načrtovanju in razvoju zaviralcev njegove aktivnosti. Na Fakulteti za farmacijo raziskujemo spojine psoralenskega tipa, katerih spojino vodnico smo odkrili z virtualnim rešetanjem ZINC knjižnice spojin. V doktorskem delu sta opisana sinteza in biokemijsko vrednotenje spojin psoralenskega tipa s spremembami na mestih 3 in 4' psoralenskega skeleta. Sintetizirali smo derivate z izboljšano selektivnostjo do [beta]5i podenote imunoproteasoma in opisali smo posledično razširjeno razmerje med strukturo in aktivnostjo spojin psoralenskega tipa. Doktorsko delo opisuje tudi načrtovanje spojin, ki bi hkrati zavirale imunoproteasom, kelirale kovinske ione ter delovale antioksidativno. Pristop hkratnega ciljanja omenjenih tarč z namenom razvoja zdravljenja nevrodegenerativnih bolezni v literaturi še ni opisan. Razvili smo inovativno pot sinteze predhodno opisanega, selektivnega in reverzibilnega zaviralca imunoproteasoma (2-cikloheksil-N-(7-(4-feniltiazol-2-il)-kinolin-2-il)sukcinaminska kislina) ter sintezo njegovega analoga z 8-hidroksikinolinskim fragmentom kot strukturnim motivom, ki omogoča kelacijo kovinskih ionov. Čeprav je uvedba 8-hidroksikinolinskega fragmenta v strukturo znanega zaviralca vodila do izgube zaviralne aktivnosti napram imunoproteasomu, predstavljajo rezultati opisanega dela dobro izhodišče za nadaljnje načrtovanje in sintezo spojin, ki bi hkrati zavirale imunoproteasom, kelirale kovinske ione ter delovale antioksidativno.Type of material - dissertation ; adult, seriousPublication and manufacture - Ljubljana : [E. Shannon Schiffrer], 2021Language - slovenianCOBISS.SI-ID - 50576131
Link(s):
Repository of the University of Ljubljana – RUL
Digitalna knjižnica Slovenije - dLib.siDostop z namenskih računalnikov v prostorih NUK
Author
Shannon Schiffrer, Eva
Other authors
Mravljak, Janez, 1978- |
Sosič, Izidor |
Perdih, Andrej, farmacevt
Topics
Nevrodegenerativne bolezni |
imunoproteasom |
načrtovanje spojin |
kelacija |
psoralen |
8-hidroksikinolin
Library/institution |
City | Acronym | For loan | Other holdings |
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Central Technological Library of the University of Ljubljana | Ljubljana | CTK |
outside loan 1 cop.
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Faculty of Pharmacy, Ljubljana | Ljubljana | FFALJ |
reading room 1 cop.
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National and University Library, Ljubljana | Ljubljana | NUK |
reading room 1 cop.
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not for loan 1 cop.
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DRS, in which the journal is indexed
Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Shannon Schiffrer, Eva | 39200 |
Mravljak, Janez, 1978- | 23419 |
Sosič, Izidor | 30816 |
Perdih, Andrej, farmacevt | 25493 |
Source: Personal bibliographies
and: SICRIS
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