Sinteza i karakterizacija harmicina, hibrida harmina i derivata cimetne kiseline, u položaju N-9 β-karbolinskog prstena

master's thesis

• Title (english): Synthesis and characterization of N-9-tethered harmicines, harmine-cinnamic acid derivate hybrids
• Author: Mislav Vrdoljak
• Mentor: Goran Poje (mentor)
• Committee member: Goran Poje (predsjednik povjerenstva)
• Committee member: Zrinka Rajić (član povjerenstva)
• Committee member: Daniela Amidžić Klarić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medicinal chemistry); Zagreb
• Defense date and country: 2023-09-22, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Multiformni glioblastom (GBM) je najčešći primarni maligni tumor mozga s medijanom preživljenja nakon dijagnoze
od samo 15 mjeseci. Liječenje ove bolesti je zahtjevno zbog pojave rezistencije tumorskih stanica na zračenje i
kemoterapiju, što dovodi do progresije i recidiva bolesti. Osim toga, postoji svega nekoliko lijekova za terapiju
multiformnog glioblastoma zbog čega je potrebno razvijati nove djelatne tvari koje bi bile učinkovitije i otpornije prema
razvoju rezistencije.
Cilj ovog diplomskog rada bila je priprava novih molekula s anti-GBM djelovanjem korištenjem principa molekulske
hibridizacije. Harmin, -karbolinski alkaloid s raznolikim biološkim djelovanjem, i derivati cimetne kiseline (DCK-i)
povezani su u jedinstvene molekule (harmicine) korištenjem bakrom(I) katalizirane azid-alkin cikloadicije (klikreakcije) uz generiranje triazolskog tipa poveznice. S obzirom da harmin i DCK-i ispoljavaju anti-GBM svojstva,
očekuje se da će pripravljeni hibridi posjedovati snažno anti-GBM djelovanje. U svrhu priprave hibrida bilo je potrebno
sintetizirati odgovarajuće prekursore: azide DCK-a 3a-c i alkin harmina 4. Alkin je sintetiziran u jednom reakcijskom
koraku, reakcijom harmina i propargil-bromida uz Cs2CO3, dok su azidi pripravljeni u četiri sintetska koraka. U prvom
koraku DCK-i su u reakciji s SOCl2, uz katalitičku količinu DMF-a, prevedeni u kiselinske kloride koji su potom
esterificirani korištenjem EtOH i TEA. Etilni esteri 1a-c reducirani su pomoću LiAlH4, a dobiveni alkoholi 2a-c
prevedeni su u azide 3a-c uz ADMP i DBU. Željeni hibridi 5a-c pripravljeni su klik-reakcijom odgovarajućih prekursora
u MeOH uz katalitičku količinu Cu(II)-acetata.
Novosintetizirani harmicini karakterizirani su uobičajenim spektroskopskim i analitičkim metodama (1H i 13C NMR,
MS i IR) te su procijenjena njihova farmakokinetička svojstva in silico. Svim harmicinima predviđa se dobra oralna
bioraspoloživost, dok se hibridima 5a-b predviđa sposobnost prolaska krvno-moždane barijere. U nastavku istraživanja
ispitat će se antiproliferativno djelovanje harmicina in vitro na humanu staničnu liniju GBM-a.

Abstract (english)

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor with a median survival time of
only 15 months. The main concern in GBM treatment is the development of resistance, which leads to disease
progression and relapse. In addition, few drugs are available for GBM chemotherapy, highlighting the need for the
development of novel and effective anti-GBM agents.
The aim of this work was to synthesize novel molecules with anti-GBM properties using the molecular hybridization
approach. Harmine, the β-carboline alkaloid with multiple biological effects, and cinnamic acid derivatives (CADs)
were linked via a triazole-type linker using a copper(I)-catalyzed azide-alkyne cycloaddition (“click” reaction) to form
a hybrid molecule. Considering that both harmine and CADs exhibit anti-GBM properties, the proposed hybrids are
expected to have a strong effect on GBM.
To prepare the target hybrids, CAD-based azides 3a-c and harmine-based alkyne 4 were synthesized. The alkyne 4 was
synthesized in one reaction step by reacting harmine with propargyl bromide in the presence of Cs2CO3, whereas the
preparation of azides 3a-c required four-step procedure. In the first step, the CADs were converted to acyl chlorides
with SOCl2 in the presence of DMF. The acyl chlorides were then esterified with ethanol and TEA, and the obtained
ethyl esters 1a-c were reduced to alcohols 2a-c with LiAlH4. Finally, the alcohols were efficiently converted to azides
3a-c with ADMP and DBU. The “click” reaction of the prepared precursors proceeded smoothly in methanol with a
catalytic amount of Cu(II) acetate and gave the desired hybrids 5a-c.
The structures of the harmicines were confirmed by standard analytical and spectroscopic methods (1H and 13C NMR,
IR and MS). The pharmacokinetic properties of harmicines were calculated in silico. Good oral bioavailability was
predicted for all harmicines. Additionally, compounds 5a-b are expected to cross the blood-brain barrier. Further studies
will investigate the antiproliferative activity of the harmicines in vitro against human GBM cell line.

• Keywords: multiformni glioblastom; harmin; derivati cimetne kiseline; klik-kemija
• Keywords (english): glioblastoma multiforme; harmine; cinnamic acid derivate; “click” chemistry
• Language: croatian
• URN:NBN: urn:nbn:hr:163:317413
• 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: 2024-01-18 14:25:22