Anelacije heterocikličnih jedinjenja i njihova primena u sintezi prirodnih proizvoda

Abstract

Cilj ove doktorske teze bio je razvoj nove sinteze protoberberinskih derivata, policikličnih jedinjenja koja sadrže izohinolinski skelet. Protoberberini predstavljaju široko rasprostranjenu, važnu grupu izohinolinskih alkaloida. Zahvaljujući njihovim izraženim farmakološkim osobinama interes za ovu grupu jedinjenja je u stalnom porastu. Novi sintetski put koji omogućuje pristup različitim klasama protoberberina baziran je na dobijanju zajedničkog intermedijera, 1,3-diena izohinolinske strukture. Diels-Alderovom reakcijom sa različitim dienofilima i oksidacijom nastalih cikloadukata omogućena je instalacija prstena C u različitim oksidacionim stanjima kao i dodatnih supstituenata potrebnih za funkcionalizaciju prstena D protoberberina. Na ovaj način dobijene su dve vrste skeleta prirodnih proizvoda, tetrahidroprotoberberinski i oksoprotoberberinski. Ova sintetska metodologija pokazala se primenljivom i na dihidro-β-karbolin i piridin. Alkaloidi koji su derivati β-karbolina su jedinjenja koja pokazuju veoma širok spektar bioloških aktivnosti, tako da postoji interes za razvoj metodologije za funkcionalizaciju ovog heterocikličnog jedinjenja. Polazeći od dihidro-β-karbolina, preko odgovarajućeg intermedijernog 1,3- diena, dobijene su dve klase jedinjenja, ketojobirinska i dihidrogambirtaninska. Piridin se takoñe pokazao pogodnim za ovu vrstu anelacija, pri čemu su dobijene benzohinolizinske strukture, slične nekim biološki aktivnim jedinjenjima. Ispitivano je in vitro citotoksično dejstvo nekih sintetisanih izohinolinskih i β- karbolinskih derivata na maligne ćelijske linije (FemX, HeLa, K562). Najznačajniju citotoksičnu aktivnost od ispitivanih jedinjenja pokazao je izohinolinski cikloadukt 2.17 prema K562 ćelijama (IC50=24,7 μM) Pored ovoga, ispitivana je funkcionalizacija 1,3-dienskog sistema paladijumom katalizovanim reakcijama, što je omogućilo dobijanje alilnih acetata sa izohinolinskom i β-karbolinskom strukturom...

The aim of this thesis was the development of a synthetic route for protoberberine derivatives, polycyclic compounds containing the isoquinoline skeleton. The protoberberines are widespread, important group of isoquinoline alkaloids. Due to the potent pharmacological properties they have attracted an attention from medicinal chemist and drug researchers. Our proposed synthetic route enabling access to different classes of protoberberines is based on a common intermediate, an isoquinolinic 1,3-diene. The incorporation of ring C in various oxidative states, as well as the incorporation of additional substituents necessary for the functionalisation of ring D of protoberberines was achieved through Diels-Alder reactions with different dienophiles and the subsequent oxidation of the resulting cycloadducts. Two types of natural products' skeletons, tetrahydroprotoberberines and oxoprotoberberines were efficiently synthesised using this approach. This synthetic methodology proved to be applicable in the preparation of dihydro-β-carbolines and pyridines. Alkaloids derived of β-carboline are important compounds with a broad spectrum of biological activities. Starting with dihydro-β-carboline, through the corresponding intermediary 1,3- diene, ketoyobirines and dihydrogambirtanines were obtained. Pyridine had also shown amenable to these types of annulations, giving benzoquinolizine structures. In vitro cytotoxic activity of some synthetised isoquinolines and β-carbolines was investigated (FemX, HeLa, K562). Cycloadduct 2.17 shows the greatest cytotoxic activity of the compounds tested, with IC50 value of 24,7 μM towards K562 cells. In addition to this, the possibility of functionalization of 1,3-diene system in Pdcatalysed reaction was also explored, enabling access to different allylic acetates with isoquinoline and β-carboline structure...