Synthesis of C-5 substituted cytosine derivatives by palladium catalysed reactions

Abstract

U ovom radu opisana je sinteza C-5 supstituiranih citozinskih derivata paladijem kataliziranim reakcijama. Sonogashira-inom reakcijom unakrsnog spajanja N-4-benzoil-5-jodcitozin (1) s terminalnim alkinima dobiveni su 5-alkinilni derivati citozina (2−4) te C-6-alkilni derivat pirolo[2,3-d]pirimidina 5. Triazolni prsten u položaj N-1 citozina uveden je „klik“ reakcijom potpomognutom mikrovalovima N-1-propagiliranog derivata citozina 6 s odgovarajućim azidima pri čemu su nastali spojevi 7−9. 5-alkinilni derivati citozina 10−11 s triazolnim supstituentom u položaju N-1 pripravljeni su Sonogashira-inom reakcijom 5-jod-N-1-metiltriazolnog derivata citozina 7 s odgovarajućim terminalnim alkinima. Strukturna karakterizacija novih derivata citozina provedena je 1H NMR spektroskopijom. Farmakološki učinci i moguće biološke mete predviđeni su in silico analizom (PASS). Citostatska ispitivanja in vitro novosintetiziranih spojeva 2, 5 i 7 provedena su na staničnim linijama HeLa (adenokarcinom vrata maternice), CaCo-2 (adenokarcinom debelog crijeva), Raji (Burkittov limfom) i K562 (kronična mijeloidna leukemija u blastičnoj fazi). Spoj 7 pokazao je umjereno djelovanje protiv stanične linije K562. Kako bi se odredili mogući mehanizmi bioloških djelovanja spojeva ispitana je interakcija spoja 7 s ct-DNA UV/Vis i fluorescencijskom spektroskopijom.This paper describes the synthesis of C-5 substituted cytosine derivatives by palladium catalysed reaction. 5-alkyl citosyne derivatives 2−4 and C-5 alkynylpyrolo[2,3-d]pirimidine derivative 6 have been synthesized by Sonogashira cross-coupling reaction of N-4-benzoyl-5-iodinecytosine (1) with terminal alkynes. N-1 triazole ring was introduced into N-1 position of cytosine derivatives 7−9 using „click“ reaction with corresponding azides under microvawe irradiation. 5-alkyl cytosine derivatives 10−11 with triazole substituent in position N-1 have been synthesized by Sonogashira cross coupling of 5-iodo-N-1-methyltriazole cytosine (7) with corresponding terminal alkyne. Structural characterization of synthesized compounds was conducted using 1H NMR spectroscopy. Pharmacological effects and potential bilogical targets of novel compounds have been predicted by in silico analysis (PASS). Cytostatic evaluation in vitro was preformed against human malignant tumor cells: HeLa, CaCo-2, Raji and K562. Compound 7 showed moderate cytotoxic effect against K562 tumor cell lines. Interaction of compound 7 with ct-DNA was performed by UV/Vis and fluorescence spectroscopy in order to predict mechanism of cytostatic activity