Sinteza i struktura novih derivata trans-(3R,4R)-amino-β-laktama te njihovo biološko testiranje na inhibiciju apsorpcije kolesterola.

doctoral thesis

• Title (english): Synthesis and structure of novel trans-(3R,4R)-amino-β-laktam derivates and their biological testing as cholesterol absorption inhibitors.
• Author: Tonko Dražić; VIAF: 305731292
• Mentor: Ivan Habuš (mentor)
• Committee member: Srđanka Tomić-Pisarović (predsjednik povjerenstva)
• Committee member: Ivanka Jerić (član povjerenstva)
• Committee member: Silva Katušić Hećimović (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2014-12-17, 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: inhibitori apsorpcije kolesterola; β-laktam; N-alkilacija; NPC1L1; srčane i krvožilne bolesti; stereoselektivna redukcija
• Keywords (english): cholesterol absorption inhibitors; coronary heart disease; β-lactam; N-alkylation; NPC1L1; stereoselective reduction
• Language: croatian
• URN:NBN: urn:nbn:hr:217:711452
• Study programme: Title: 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 resource: Text
• Extent: 129 str. ; 30 cm
• File origin: Born digital
• Access conditions: Closed access
• Created on: 2019-03-21 17:14:30