Priprava novih potencijalnih NOD2 agonista s lipofilnim tripeptidnim motivom

master's thesis

• Title (english): Preparation of novel potential NOD2 agonists with lipophilic tripeptide motive
• Author: Karla Čižmešija
• Mentor: Željka Car (mentor)
• Committee member: Željka Car (predsjednik povjerenstva)
• Committee member: Mirta Rubčić (član povjerenstva)
• Committee member: Ivan Nemet (član povjerenstva)
• Committee member: Vesna Petrović Peroković (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2024-10-22, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

U sklopu ovog diplomskog rada razvijen je sintetski put priprave tripeptidnih derivata ferocena, potencijalnih NOD2 agonista. Ciljni spojevi 6, 8 i 9 sintetizirani su kondenzacijom prethodno pripravljenog tripeptidnog motiva 5 s kiselinskim derivatima ferocena (ferocenkarboksilnom kiselinom, spojem 7 i ferocenoctenom kiselinom). Amidna veza ostvarena je pomoću pouzdane EDC/HOBt metode. Spoj 7 dobiven je reakcijom saponifikacije iz odgovarajućeg esterskog prekursora. Sinteza spoja 5 provedena je u nekoliko koraka. Polazna D-glutaminska kiselina najprije je esterificirana u dietilni ester 1 te kondenzirana s L-valinom čime je dobiven Boc-zaštićeni dipeptid 2. Ispitana su tri načina kondenzacije pri čemu se N-hidroksisukcinimidna metoda pokazala najučinkovitijom. Uklanjanjem Boc-zaštitne skupine uz trifluoroctenu kiselinu uspješno je pripravljen TFA- dipeptid 3. Spoj 3 je kondenziran s Boc-zaštićenim glicinom EDC/HOBt metodom uz trietilamin te uspješno proveden u Boc-zaštićeni tripeptid 4. Uklanjanjem Boc-zaštitne skupine uz TFA pripravljen je tripeptid 5. Provedena je strukturna karakterizacija svih sintetiziranih spojeva (1H, DEPTQ NMR i spektrometrija masa ESI-MS). Ciljne molekule 6, 8 i 9 pokazuju značajnu agonističku aktivnost na HEK-Blue NOD2 stanicama.

Abstract (english)

In this Thesis, the synthetic route for the preparation of tripeptide derivatives of ferrocene, potential NOD2 agonists, was optimized. The target compounds 6, 8 and 9 were synthesized by condensation of the previously prepared tripeptide motif 5 and the corresponding ferrocene acid derivatives (ferrocenecarboxylic acid, compound 7 and ferrocenacetic acid). The amide bond was formed using the reliable EDC/HOBt method. Compound 7 was prepared by saponification from corresponding ester precursor. Synthesis of compound 5 was conducted in several steps. Starting D-glutamic acid was converted into diethyl ester 1 first and coupled with L-valine resulting in Boc-protected dipeptide 2. Three condensation methods were investigated with N-hydroxysuccinimide method being the most efficient one. Boc-protecting group was removed with trifluoroacetic acid and TFA dipeptide 3 was successfully prepared. Compound 3 was converted into Boc-protected tripeptide 4 by condensation with Boc-protected glycine using the EDC/HOBt method and triethylamine. Removal of Boc protection yielded tripeptide 5. Structural characterization of all compounds was performed by 1H and DEPTQ NMR spectroscopy as well as mass spectrometry (ESI-MS). Target molecules 6, 8 and 9 show high NOD2 agonistic activity on HEK-Blue NOD2 cells.

• Keywords: adjuvant; desmuramil-peptid; ferocen; NOD2 agonist; tripeptid
• Keywords (english): adjuvant; desmuramyl peptide; ferrocene; NOD2 agonist; tripeptide
• Language: croatian
• URN:NBN: urn:nbn:hr:217:272712
• Project: Number: IP-2020-02-9162; Title: Ferocenski analozi biomolekula: strukturna karakterizacija i biološka evaluacija; Title: Ferrocene analogues of biomolecules: structural characterization and biological evaluation; Acronym: FER-AN-BIOMOL; Leader: Lidija Barišić; Jurisdiction: Croatia; Funder: Hrvatska zaklada za znanost; Funding stream: Research Projects
• Study programme: Title: Graduate university studies in chemistry; specializations in: Graduate university studies in chemistry; Course: Graduate university studies in chemistry; Study programme type: university; Study level: graduate; Academic / professional title: sveučilišni/a magistar/magistra kemije (sveučilišni/a magistar/magistra kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2024-11-04 13:41:12