Načrtovanje in sinteza derivatov psoralen-3-ocetne kisline kot zaviralcev imunoproteasoma

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Jezik:	Slovenski jezik
Leto izida:	2015
Tipologija:	2.09 - Magistrsko delo
Organizacija:	UL FFA - Fakulteta za farmacijo
Založnik:	[N. Erdani]
UDK:	615.2:616-097
COBISS:	3942513
Št. ogledov:	1083
Št. prenosov:	254
Ocena:	0 (0 glasov)
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Sekundarni jezik:	Angleški jezik
Sekundarni naslov:	Design and synthesis of psoralen-3-acetic acid derivatives as immunoproteasome inhibitors
Sekundarni povzetek:	The ubiquitin proteasome system is the major cellular system for the regulated degradation of short-lived, damaged or defectively folded cytoplasmic proteins. It consists of the ubiquitination system, which selects and targets proteins, and the proteasome that performs the degradation. The immunoproteasome is a variant form of the standard proteasome. Immune system cells express a higher level of immunoproteasome, while in other cells, oxidative stress and proinflammatory cytokines are the stimuli that lead to elevated production of immunoproteasome. Upon induction, the immunoproteasome catalytic subunits: caspase-like, trypsin-like and chymotrypsin-like subunit, are synthesized and incorporated, replacing their standard proteasome counterparts β1, β2 and β5, respectively. Although the immunoproteasome is thought to be specialized in the generation of major histocompatibility complex class I antigenic peptides with hydrophobic C-terminal residues, increasing evidence indicates additional non-immune functions. Elevated levels of immunoproteasome catalytic subunits have been also observed in certain disease states, such as cancer, inflammatory bowel disease and neurodegenerative diseases. For all these reasons immunoproteasome is becoming an interesting pharmacological target. In the presented work, we successfully designed, synthesized and structurally characterized twelve new compounds with inhibitory activity on the chymotrypsin-like catalytic subunit of the immunoproteasome. All of the synthesized compounds were based on a psoralen scaffold, on which structural changes were introduced at the positions 3 and 4'. The synthesis of final products was performed in several consecutive reaction steps. First, we synthesized 7-hydroxycoumarin ring by reacting resorcinol with diethyl 2- acetylsuccinate and concurrently performed the alpha bromination of selected heterocyclic ketone derivates. Then, the alpha brominated ketones were introduced to properly modify the hydroxyl group of the 7-hydroxycoumarin ring. In the next stage, the condensation reaction was performed leading to the formation of the psoralen-3-acetic acid derivatives. Finally, the carboxylic acid of the prepared compounds was transformed into activated esters and N-cyanomethylamides. These can form a covalent interaction with the threonine in the active site of the immunoproteasome. At the Department of the Clinical Biochemistry, the inhibitory activity of the synthesized products was evaluated. This was performed by determination of the residual activity of the chymotrypsin-like activity of the immunoproteasome in the presence of inhibitors. We have discovered that compounds with 2,5-dimethylthiophene heteroaromatic system at the position 4' of the psoralen ring and an activated succinimidyl ester show the best inhibitory activity. The most potent inhibitor in the presented series was compound, which possessed both above-mentioned fragments in its structure.
Sekundarne ključne besede:	Kemometrija;
Vrsta dela (COBISS):	Magistrsko delo/naloga
Komentar na gradivo:	Univ. Ljubljana, Fak. za farmacijo
Strani:	IV, 58 f.
ID:	12050944