Sinteza i karakterizacija amidnog prolijeka tafamidisa

master's thesis

• Title (english): Synthesis and characterization of tafamidis amide prodrug
• Author: Nikola Grus
• Mentor: Kristina Pavić (mentor)
• Committee member: Kristina Pavić (predsjednik povjerenstva)
• Committee member: Ana Babić Perhoč (član povjerenstva)
• Committee member: Lidija Bach-Rojecky (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry); Zagreb
• Defense date and country: 2024-06-06, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Ovaj rad dio je istraživanja provedenog u Zavodu za farmaceutsku kemiju Farmaceutsko-biokemijskog fakulteta Sveučilišta u Zagrebu u sklopu projekta Uloga transtiretina u leptomeningealnoj i cerebrovaskularnoj amiloidozi povezanoj sa sporadičnom Alzheimerovom bolesti i neuroprotektivni potencijal prolijeka tafamidisa – TransADamis Medicinskog fakulteta Sveučilišta u Zagrebu koji obuhvaća sintezu i in vivo ispitivanje sposobnosti amidnog prolijeka tafamidisa da stabilizira transtiretin (TTR) u središnjem živčanom sustavu i ublaži streptozotocinom induciranu neurodegeneraciju i kognitivni deficit.
Cilj ovog rada bila je sinteza i karakterizacija amidnog prolijeka tafamidisa. Sinteza je započeta prevođenjem karboksilne kiseline tafamidisa do odgovarajućeg piperazinskog amida 1 s tert-butiloksikarbonilnom zaštitnom skupinom nakon čega je zaštitna skupina hidrolizirana čime je dobiven konačni produkt 2.
Strukture svih sintetiziranih spojeva potvrđene su uobičajenim analitičkim i spektroskopskim metodama (FT-IR, 1H i 13C NMR, MS), a relativna čistoća određena je pomoću tekućinske kromatografije visoke djelotvornosti (HPLC). Konačni produkt u potpunosti zadovoljava Lipinskijeva i Veberova pravila koja se koriste za predviđanje oralne bioraspoloživosti lijekova. Također, web alat SwissADME predviđa visoku oralnu bioraspoloživost i mogućnost prelaska KMB-a amida 2 što je u skladu s rezultatima prethodno objavljene studije in vivo.
Učinak amida 2 na stabilizaciju TTR-a u središnjem živčanom sustavu i ublažavanje neurodegeneracije bit će ispitan u daljnjim istraživanjima koja prelaze okvire ovog rada.

Abstract (english)

This work is part of the research conducted at the Department of Pharmaceutical Chemistry, University of Zagreb Faculty of Pharmacy and Biochemistry, within the project Role of Transthyretin in Leptomeningeal and Cerebrovascular Amyloidosis Associated with Sporadic Alzheimer's Disease and the Neuroprotective Potential of Tafamidis Prodrug – TransADamis of the School of Medicine, University of Zagreb, which encompasses the synthesis and in vivo testing of the ability of the amide prodrug of tafamidis to stabilize transthyretin (TTR) in the central nervous system and mitigate streptozotocin-induced neurodegeneration and cognitive deficit.
The aim of this thesis was the synthesis and characterization of the amide prodrug of tafamidis. The synthesis began with the conversion of tafamidis carboxylic acid to the corresponding piperazine amide 1 with a tert-butoxycarbonyl protecting group, followed by hydrolysis of the protecting group to obtain the final product 2.
The structures of all synthesized compounds were confirmed by standard analytical and spectroscopic methods (FT-IR, 1H and 13C NMR, MS), and the relative purity was determined by high-performance liquid chromatography (HPLC). The final product fully complies with Lipinski's and Veber's rules used to predict the oral bioavailability of drugs. Additionally, the web tool SwissADME predicts high oral bioavailability and the ability of amide 2 to cross the blood-brain barrier, which is consistent with the results of a previously published in vivo study. The effect of amide 2 on the stabilization of TTR in the central nervous system and the mitigation of neurodegeneration will be examined in further research beyond the scope of this paper.

• Keywords: tafamidis; Alzheimerova bolest; transtiretin; amidni prolijek
• Keywords (english): tafamidis; Alzheimer's disease; transthyretin; amide prodrug
• Language: croatian
• URN:NBN: urn:nbn:hr:163:998564
• Study programme: Title: Pharmacy - integrated undergraduate and graduate - university study; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: sveučilišni magistar farmacije (sveučilišni magistar farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2024-09-20 12:36:11