Synthesis and structure of novel trans-(3R,4R)-amino-β-laktam derivates and their biological testing as cholesterol absorption inhibitors

Dražić, Tonko (2014) Synthesis and structure of novel trans-(3R,4R)-amino-β-laktam derivates and their biological testing as cholesterol absorption inhibitors. Doctoral thesis, Faculty of Science > Department of Chemistry.

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Abstract

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.

Item Type: Thesis (Doctoral thesis)
Keywords: cholesterol absorption inhibitors, coronary heart disease, β-lactam, N-alkylation, NPC1L1, stereoselective reduction
Supervisor: Habuš, Ivan
Date: 2014
Number of Pages: 129
Subjects: NATURAL SCIENCES > Chemistry
Divisions: Faculty of Science > Department of Chemistry
Depositing User: mag. bibl. Ana Šafran
Date Deposited: 12 Jan 2015 13:00
Last Modified: 14 Oct 2015 08:04
URI: http://digre.pmf.unizg.hr/id/eprint/3589

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