Sinteza konjugata manozne i O-glikolil-desmuramilpeptida

master's thesis

• Title (english): Synthesis of O-glycolyl desmuramylpeptide mannoconjugates
• Author: Doroteja Pavić
• Mentor: Rosana Ribić (mentor)
• Committee member: Vesna Petrović Peroković (predsjednik povjerenstva)
• Committee member: Željka Soldin (član povjerenstva)
• Committee member: Sanda Rončević (član povjerenstva)
• Committee member: Srđanka Tomić-Pisarović (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2016-12-15, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

Muramildipeptid (MDP), N-acetilmuramil-L-alanil-D-izoglutamin, fragment je peptidoglikana koji pojačava imunološki odgovor na specifični antigen. MDP se klinički ne upotrebljava zbog pirogenosti i brze eliminacije te se pripravljaju novi derivati s poboljšanim farmakološkim svojstvima. Osobito se ističu lipofilniji derivati MDP-a poput desmuramildipeptida (derivata bez šećerne podjedinice). Nadalje, dobre rezultate pokazali su manozni analozi MDP-a koji vjerojatno radi interakcije s manoznim receptorima imunokompetentnih stanica pokazuju pojačanu aktivnost.
U okviru ovog diplomskog rada sintetizirani su novi konjugati manoze i O-glikolil-desmuramildipeptida koji se međusobno razlikuju po skupinama vezanima na C-kraju peptida (hidroksilna, adamantilna i adamantil-triazolna). Prvo je sintetizirana 2-(2,3,4,6-tetra-O-acetil-α-D-manopiranoziloksi)octena kiselina supstitucijom broma iz t-butil-bromacetata s tetraacetiliranom manozom α-konfiguracije. Dobivenom manozidu je uklonjena esterska zaštita s karboksilne skupine preko koje je potom karbodiimidnom metodom uz EDC/HOBt aktivaciju vezan desmuramildipeptid s odgovarajućom skupinom na C-kraju. U posljednjoj fazi selektivno su uklonjene zaštitne acetatne skupine s manozne podjedinice. Svi sintetizirani spojevi su strukturno okarakterizirani NMR spektroskopijama, spektrometrijom masa, a neki od njih i IR spektroskopijom.

Abstract (english)

Muramyl dipeptide (MDP), N-acetylmuramyl-L-alanyl-D-isoglutamine, is the fragment of peptidoglycan which added to vaccines prolongate or enhance a specific immune response to a specific antigen. Since MDP can not be clinically used because side effects such as pyrogenic activity, numerous MDP derivatives and analogues with improved pharmacological properties were synthesized, including derivatives without sugar part known as desmuramydipeptides. Furthermore, mannose analogues of MDP have showed better adjuvant activity, probably due to interactions of mannose with mannose receptors present on immunocompetent cells.
In the scope of this Diploma Thesis novel desmuramylpeptide mannocojugates with potential adjuvant activity were synthesized. Desmuramylpeptide mannoconjugates have different groups (hydroxy, adamantyl, adamantyl triazole) attached to carboxy group in C-terminus. First 2-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl)acetic acid was synthesized. The bromine in tert-butyl bromoacetate was substituted with the 2,3,4,6-tetra-O-acetyl-α-D-mannopyranose. Ester group of the prepared O-mannoside was hydrolyzed and obtained carboxylic acid was then coupled to corresponding desmuramyldipeptide derivative using EDC / HOBt carbodiimide method. In the last step protective groups from mannose were selectively removed. All the synthesized compounds were characterized by NMR spectroscopy and mass spectrometry, and some of them were additionaly analyzed by IR spectroscopy.

• Keywords: adamantan; adjuvant; desmuramildipeptid; manoza
• Keywords (english): adamantine; adjuvant; desmuramyldipeptide; mannose
• Language: croatian
• URN:NBN: urn:nbn:hr:217:663767
• Study programme: Title: Graduate university studies in chemistry; specializations in: Research programme; Course: Research programme; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra kemije (magistar/magistra kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2018-12-15
• Created on: 2017-03-22 09:54:40