Faculty of Pharmacy, Lj. (FFALJ)
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Sinteza in vrednotenje substituiranih 1H-benzo[d]imidazol-2-karbonitrilov in 2-cianobenzo[d]oksazolkarboksilatov kot kovalentnih zaviralcev imunoproteasoma = Synthesis and evaluation of 1H-benzo[d]imidazole-2-carbonitriles and 2-cyanobenzo[d]oxazolecarboxylates as covalent inhibitors of immunoproteasome : Uniform Master's Study Programme PharmacyKrajnc, Tina, farmacevtkaUbikvintin-proteasomski sistem je pomemben za zagotavljanje homeostaze proteinov v celicah, saj je odgovoren za razgradnjo napačno zvitih in poškodovanih proteinov. Raziskave so pokazale, da se pri ... avtoimunskih boleznih, raku in nevrodegenerativnih spremembah pod vplivom vnetnih citokinov poveča izražanje imunoproteasoma, zaradi česar se je v zadnjem desetletju povečal obseg raziskav na področju selektivnih zaviralcev imunoproteasoma, ki imajo, v primerjavi z neselektivnimi zaviralci, manj neželenih učinkov. V okviru magistrske naloge smo se osredotočili na sintezo 2-cianobenzimidazolov in 2-cianobenzoksazolov, ki so heterobicikli z elektrofilno bojno glavo – nitrilom. Ciano skupina lahko tvori kovalentno vez s Cys48 v 5i podenoti imunoproteasoma, kar omogoča selektivno zaviranje 5i podenote imunoproteasoma, saj 5c konstitutivna podenota proteasoma na tem mestu nima cisteinskega aminokislinskega preostanka. Pri sintezi smo izhajali iz substituiranih orto-fenilendiaminov oziroma 2-aminofenolov, kjer je v prvi stopnji potekala ciklizacija med dinukleofilom in Appelovo soljo. Sintetizirane 2-cianobenzimidazole smo v drugem koraku z uporabo metil jodida pretvorili do dveh položajnih izomerov 2-ciano-N-metilbenzimidazola, ki smo ju očistiti in ločiti s kolonsko kromatografijo, strukturo posameznega položajnega izomera pa smo potrdil z 2-dimenzionalnimi eksperimenti jedrske magnetne resonance. Metil karboksilate 2-cianobenzoksazolov smo pretvorili do karboksilnih kislin z in situ pripravljeno Lewisovo kislino aluminijev trijodid (AlI3) v brezvodnih pogojih, da smo se izognili hidrolizi aktiviranega nitrila. Rezultati biokemijskega testiranja spojin na 5i podenoti imunoproteasoma so razkrili, da spojine 1, 2, 4B, 7–10 zavirajo imunoproteasom, najmočnejši zaviralec pa je bila spojina 7 z IC50 vrednostjo 12 ± 1 µM. 2-Cianobenzoksazoli so v splošnem močnejši zaviralci kot 2-cianobenzimidazoli, vendar so slednji zaradi boljše stabilnosti in manjše reaktivnosti lahko boljša osnova za nadaljnjo optimizacijo nizkomolekularnih zaviralcev 5i podenote imunoproteasoma.Type of material - master's thesis ; adult, seriousPublication and manufacture - Ljubljana : [T. Krajnc], 2022Language - slovenianCOBISS.SI-ID - 121811203
Author
Krajnc, Tina, farmacevtka
Other authors
Knez, Damijan, farmacevt |
Gobec, Martina, 1983-
Topics
Avtoimunske bolezni |
Farmacevtska kemija |
benzimidazol |
benzoksazol |
imunoproteasom |
kovalentni zaviralci |
nitril |
sinteza 2-cianobenzimidazolov |
sinteza 4-kloro-1H-benzo[d]imidazol-2-karbonitrila
Call number – location, accession no. ... |
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Knjižnica emšf 0000000615 KRAJNC TINA Sinteza 0000001126 IN: 0017363 Knjižnica emšf 615 KRAJNC TINA Sinteza 1126 IN: 0017363 |
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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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Krajnc, Tina, farmacevtka | |
Knez, Damijan, farmacevt | 36438 |
Gobec, Martina, 1983- | 32034 |
Source: Personal bibliographies
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