Annulations of heterocyclic compounds and their application in synthesis of natural compounds

Abstract

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 1,3diene, 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 IC 50 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. A synthetic route to benzazepine derivatives of isoquinoline, β-carboline and pyridine was also developed and some of the compounds obtained have shown a substantial protective effect on the DNA of human lymphocites, surpassing that of a commercial radioprotective agent amifostine. In vitro cytotoxic activity against cancer cell lines some synthetised benzazepine was tested (FemX, HeLa, K562). IC 50 Values of benzazepine derivatives range of 17,49-74,70 µM.