Sinteza i karakterizacija novih N-triazolskih derivata beta-karbolina i cimetne kiseline

master's thesis

• Title (english): Synthesis and characterization of novel N-triazole derivates of beta-carboline and cinnamic acid
• Author: Luka Tomašić
• Mentor: Ivana Perković (mentor)
• Committee member: Ivana Perković (predsjednik povjerenstva)
• Committee member: Zrinka Rajić (član povjerenstva)
• Committee member: Miranda Sertić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry); Zagreb
• Defense date and country: 2019-07-09, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Pregled literature o prirodnim spojevima koji posjeduju antimalarijsko djelovanje pokazao je da harmin, β-karbolinski alkaloid ima potvrđeno in vivo i in vitro antimalarijsko djelovanje. Mogući mehanizam djelovanja harmina je inhibicija P. falciparum Hsp90, koji ima važnu ulogu u razvoju rezistencije na liječenje. U ovom radu opisana je sinteza i karakterizacija novih derivata β-karbolina i cimetne kiseline povezanih 1,2,3-triazolskim mostom s ciljem optimizacije β-karbolinske strukture dobivanja derivata poboljšanog djelovanja. Kao početni spoj u sintezi korišten je metilni ester triptofana, koji je Pictet-Spenglerovom reakcijom u mikrovalnom reaktoru preveden u tetrahidro-β-karbolinski spoj 5. Njegovom oksidacijom uz Pd/C i Li2CO3 dobiven je ester 6 koji je redukcijom s LiAlH4 preveden u odgovarajući alkohol (7). Dobiveni β-karbolinski alkohol je u reakciji s propargil bromidom preveden u N-propargilirani derivat 8. U klik reakciji azid-alkin cikloadicije katalizirane bakrom N-propargiliranog derivata 8 i prethodno sintetiziranih azida cimetne 1, odnosno p-metoksicimetne kiseline 4 dobivena su dva 1,2,3-triazolska derivata (9, 10). Strukture sintetiziranih spojeva potvrđene su uobičajenim analitičkim i spektroskopskim metodama (tt, MS, IR, 1H i 13C NMR). Sintetiziranim derivatima β-karbolina 9, 10 će u daljnim istraživanjima biti ispitano biološko djelovanje.

Abstract (english)

The literature survey revealed a natural product found in several plants, β-carboline alcaloid harmine, to possess in vivo and in vitro antimalarial activity. Assumed mechanism of action is inhibition of P. falciparum Hsp90, which has an important role in the development of antimalarial resistance. This research describes synthesis and characterization of two new derivates of β-carboline and cinnamic acid linked with 1,2,3-triazole bridge, with the aim of optimizing β-carboline structure in order to achieve increased and more selective antimalarial activity. The initial compound in the synthesis sequence was tryptophan methyl ester, which was converted into tetrahydro-β-carboline 5 compound in Pictet-Spengler reaction. Further oxydation with Pd/C and Li2CO3 gave the appropriate ester 6, which was reduced to corresponding alcohol 7. The β-carboline alcohol 7 was then converted into N-propargilated derivate 8 in the reaction with propargyl bromide. Cooper-catalyzed alkyne-azide cycloadition click reaction of the N-propargilated derivate 8 and previously synthethized azides of cinnamic (1) and p-methoxy cinnamic acid (4) gave the final compounds 1,2,3-triazole derivates (9, 10). Structures of synthetized compounds were confirmed the usual analytical and spectroscopic methods (mp, MS, IR, 1H and 13C NMR). Antimalarial activity of synthetized harmine derivates 9 and 10 will be tested.

• Keywords: β-karbolin; cimetna kiselina; Hsp90; cikloadicija; 1; 2; 3-triazol
• Keywords (english): β-carboline; cinnamic acid; Hsp90; cycloadition; 1; 2; 3-triazole
• Language: croatian
• URN:NBN: urn:nbn:hr:163:390865
• Study programme: Title: Pharmacy; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: magistar/magistra farmacije (magistar/magistra farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2021-09-07 13:37:29