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Sinteza i struktura novih derivata trans-(3R,4R)-amino-β-laktama te njihovo biološko testiranje na inhibiciju apsorpcije kolesterola.
Zagreb: University of Zagreb, Faculty of Science, 2014. urn:nbn:hr:217:711452
Dražić, Tonko
University of Zagreb
Faculty of Science
Department of Chemistry

Institutional repository: Repository of the Faculty of Science

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Dražić, T. (2014). Sinteza i struktura novih derivata trans-(3R,4R)-amino-β-laktama te njihovo biološko testiranje na inhibiciju apsorpcije kolesterola. (Doctoral thesis). Zagreb: University of Zagreb, Faculty of Science. Retrieved from https://urn.nsk.hr/urn:nbn:hr:217:711452

Dražić, Tonko. "Sinteza i struktura novih derivata trans-(3R,4R)-amino-β-laktama te njihovo biološko testiranje na inhibiciju apsorpcije kolesterola.." Doctoral thesis, University of Zagreb, Faculty of Science, 2014. https://urn.nsk.hr/urn:nbn:hr:217:711452

Dražić, Tonko. "Sinteza i struktura novih derivata trans-(3R,4R)-amino-β-laktama te njihovo biološko testiranje na inhibiciju apsorpcije kolesterola.." Doctoral thesis, University of Zagreb, Faculty of Science, 2014. https://urn.nsk.hr/urn:nbn:hr:217:711452

Dražić, T. (2014). 'Sinteza i struktura novih derivata trans-(3R,4R)-amino-β-laktama te njihovo biološko testiranje na inhibiciju apsorpcije kolesterola.', Doctoral thesis, University of Zagreb, Faculty of Science, accessed 28 December 2024, https://urn.nsk.hr/urn:nbn:hr:217:711452

Dražić T. Sinteza i struktura novih derivata trans-(3R,4R)-amino-β-laktama te njihovo biološko testiranje na inhibiciju apsorpcije kolesterola. [Doctoral thesis]. Zagreb: University of Zagreb, Faculty of Science; 2014 [cited 2024 December 28] Available at: https://urn.nsk.hr/urn:nbn:hr:217:711452

T. Dražić, "Sinteza i struktura novih derivata trans-(3R,4R)-amino-β-laktama te njihovo biološko testiranje na inhibiciju apsorpcije kolesterola.", Doctoral thesis, University of Zagreb, Faculty of Science, Zagreb, 2014. Available at: https://urn.nsk.hr/urn:nbn:hr:217:711452

Metadata
TitleSinteza i struktura novih derivata trans-(3R,4R)-amino-β-laktama te njihovo biološko testiranje na inhibiciju apsorpcije kolesterola.
Title (english)Synthesis and structure of novel trans-(3R,4R)-amino-β-laktam derivates and their biological testing as cholesterol absorption inhibitors.
AuthorTonko Dražić
VIAF: 305731292
MentorIvan Habuš (mentor)
Committee memberSrđanka Tomić-Pisarović (predsjednik povjerenstva)
Committee memberIvanka Jerić (član povjerenstva)
Committee memberSilva Katušić Hećimović (član povjerenstva)
GranterUniversity of Zagreb
Faculty of Science
(Department of Chemistry)
Zagreb
Defense date and country2014-12-17, Croatia
Scientific / art field,
discipline and subdiscipline		NATURAL SCIENCES
Chemistry
Universal decimal classification
(UDC)		54 - Chemistry. Crystallography. Mineralogy
Abstract
β-Laktamski spojevi pokazuju značajnu aktivnost kao inhibitori apsorpcije kolesterola. Cilj doktorske disertacije bio je sintetizirati derivate β-laktama koji na C-3 položaju imaju amino skupinu, te ispitati njihovu učinkovitost u inhibiciji apsorpcije kolesterola. Enantiomerno čisti trans-3-amino-β-laktam dobiven je reakcijom ciklokondenzacije mentilnog estera glicina s iminom. N-alkilacijom amino skupine β-laktama s odgovarajućim alkil-halogenidima, te stereoselektivnom redukcijom karbonilne skupine pripravljena su dva aminoalkoholna analoga ezetimiba. Pritom su ispitane dvije metode sinteze kojima su, osim čistih dijastereoizomera, dobivene i dijastereoizomerne smjese u omjeru 70:30 i 85:15. Rentgenskom strukturnom analizom određena je apsolutna konfiguracija na novoformiranim kiralnim centrima na pobočnom lancu aminoalkohola, te je utvrđeno da su novi kiralni centri (S)-konfiguracije. pKa vrijednost sekundarne amino skupine oba aminoalkohola iznosi 9,35, što znači da se u tankom crijevu i krvi nalaze u obliku amonijevih soli. Također, reakcijom β-laktama s odgovarajućim acil-kloridima sintetizirano je šest amidnih analoga ezetimiba. Aktivnost novih spojeva kao inhibitora apsorpcije kolesterola ispitana je in vitro pomoću [3H]kolesterola na Madin-Darby Canine Kidney II (MDCKII) staničnoj liniji koja stabilno eksprimira ljudski Niemann-Pick C1-like1 (NPC1L1) protein. In vivo inhibicija akutne apsorpcije kolesterola ispitana je na C57BL/6 miševima. Svi novosintetizirani spojevi pokazali su značajnu in vitro aktivnost, dok su in vivo aktivnost pokazali aminoalkoholni analozi ezetimiba. Time se pokazalo da 3-amino-β-laktamski spojevi mogu biti učinkoviti inhibitori apsorpcije kolesterola.
Abstract (english)
β-Lactam compounds are strong cholesterol absorption inhibitors. The goal of this dissertation was to synthesize β-lactam derivatives containing amino group at C-3 position and test their inhibitory activity . Enantiopure trans-3-amino-β-lactam was synthesized using cyclocondensation reaction of glycine menthyl ester with imine. Two amino alcohol ezetimibe analogs were prepared from β-lactam using N-alkylation reaction on β-lactam amino group with corresponding alkyl halogenides, as well as stereoselective reduction of carbonyl group. The two methods for the preparation of new amino alcohols were examined. Besides pure compounds, they gave diastereoisomeric mixtures in ratio 70:30 and 85:15. The absolute configurations on two new side chain chiral centres were resolved, and both were assigned to be (S)-. The pKa value for both new compounds was determined to be 9,35, indicating that they are in the form of ammonium salt in blood and small intestine. Furthermore, six new amide ezetimibe analogs were synthesized from β-lactam and the corresponding acyl chlorides. In vitro and in vivo biological activity of all new compounds as cholesterol absorption inhibitors was tested. Madin-Darby Canine Kidney II (MDCKII) cell line stably expressing human Niemann-Pick C1-like1 (NPC1L1) protein was used for in vitro studies and protocol for [3H]cholesterol uptake was established. In vivo activity of the compounds was tested in C57BL/6 mice. All new ezetimibe analogs showed significant in vitro cholesterol absorption inhibitory activity, whereas only amino alcohol analogs showed in vivo activity. Therefore, we have shown that 3-amino-β-lactam compounds are efficient cholesterol absorption inhibitors.
Keywords
Keywords (english)
Languagecroatian
URN:NBNurn:nbn:hr:217:711452
Study programmeTitle: Doctoral study in chemistry
Study programme type: university
Study level: postgraduate
Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija (doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija)
Type of resourceText
Extent129 str. ; 30 cm
File originBorn digital
Access conditionsClosed access
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Created on2019-03-21 17:14:30