Anelacije heterocikličnih jedinjenja i njihova primena u sintezi prirodnih proizvoda
Annulations of heterocyclic compounds and their application in synthesis of natural compounds
Author
Simić, Milena R.
Mentor
Savić, Vladimir
Committee members
Tešević, Vele
Pavlović, Vladimir

Maslak, Veselin

Stanković, Miroslava
Metadata
Show full item recordAbstract
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
applic...able 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...