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Sinteza in vrednotenje hidroksimetilkarbonilnih analogov prehodnega stanja kot potencialnih inhibitorjev D-alanil-D-alanin ligaze = Synthesis and evaluation of hydroxymethylcarbonyl transition-state analogs as potential inhibitors of D-alanyl-D-alanine ligase : diplomska nalogaAjd, MartinaOdkritje antibiotikov pomeni enega najpomembnejsih mejnikov v razvoju in napredku medicine. Vendar njihova uporaba ni samo moèno zmanjsala smrtnosti zaradi infekcijskih bolezni, ampak na zalost tudi ... postopno razvila vse veè bakterijskih sevov, ki so odporni (rezistentni) proti posameznim ali celo veè razliènim antibiotikom. Selekcijo odpornih bakterijskih sevov namreè omogoèa predvsem mnozièna in mnogokrat nekritièna uporaba antibiotikov. Ravno zaradi razvoja rezistence obstaja potreba po novih in bolj uèinkovitih protibakterijskih uèinkovinah. Sinteza peptidoglikana je bogat vir novih encimskih tarè za protibakterijsko zdravljenje. Med temi encimi je tudi D-alanil-D-alanin ligaza (Ddl). Ddl katalizira sintezo dipeptida D-alanil-D-alanina, ki se pripne na UDP-N-acetilmuramil tripeptid. Dipeptid jemesto, kjer pride do premrezenja med sosednjima glikanskima verigama peptidoglikana, hkrati pa je tudi vezavno mesto za antibiotik vankomicin. Mehanizem katalize poteka preko tetraedriènega intermediata. Edini znani inhibitor Ddl, ki se uporablja v terapiji, je D-cikloserin. V okviru diplomskenaloge smo uspesno sintetizirali serijo hidroksimetilkarbonilnih analogov prehodnega stanja DdlČ 6, 10, 11, 12, 14, 15, 16, 18, 19, 20, 22, 23 in 24. Pri njihovi sintezi je bila glavni intermediat -hidroksi- -aminokislina (izotreonin). Sintezni postopek za pripravo -hidroksi- -aminokislin je v literaturi dobro opisan. Izhajali smo iz s terc-butiloksikarbonilno skupino (Boc) zasèitenega D-alanina, ki smo ga pretvorili v Weinrebov amid. Tega smo z LiAlH4 reducirali do Boc-D-alaninala. Iz aldehida smo pripravili terc-butil (2R)-1-ciano-1-hidroksipropan-2-ilkarbamat, po hidrolizi slednjega pa smo dobili -hidroksi- -amino derivat alanina (izotreonin). S pomoèjo sulfonilkloridov smo na N-terminalni del izotreonina uvedli aromatske fragmente ter na nastale produkte pripeli benzilni ester D-alanina. V drugem primeru pa smo izotreoninu najprej zasèitili amino skupino ter ga nato sklopili z benzilnim estrom D-alanina. Sledila je se odstranitev zasèitnih skupin.S pomoèjo bioloskih testov smo sintetiziranim spojinam doloèili njihovoinhibitorno aktivnost na DdlB iz E.coli. Sam -hidroksi- -amino derivatalanina (izotreonin) 6 je imel sibko inhibitorno aktivnost, vendar le po predinkubaciji. Kakrsnakoli substitucija ni doprinesla k izboljsanju inhibitorne aktivnostiType of material - undergraduate thesisPublication and manufacture - Ljubljana : [M. Ajd], 2007Language - slovenianCOBISS.SI-ID - 2112625
Author
Ajd, Martina
Other authors
Gobec, Stanislav, 1970- |
Kovač, Andreja, farmacevtka, 1979-
Topics
D-alanil-D-alanin ligaze |
peptidomimetiki |
sinteza |
biološko testiranje spojin |
analogi prehodnega stanja
Library | Call number – location, accession no. ... | Copy status |
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Faculty of Pharmacy, Lj. | Knjižnica dp 615 Ajd Martina Sinteza in IN: 0009495 |
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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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Ajd, Martina | |
Gobec, Stanislav, 1970- | 15284 |
Kovač, Andreja, farmacevtka, 1979- | 27782 |
Source: Personal bibliographies
and: SICRIS
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