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Nukleozidi i njihovi analozi imaju značajnu ulogu u otkrivanju i razvoju lijekova zbog svojih izuzetnih kemoterapijskih aktivnosti, stoga je sintetizirano niz strukturno različitih nukleozida. Prisutnost više nukleofilnih mjesta u nukleobazama sa sličnom reaktivnošću u reakciji N-alkiliranja i N-aciliranja daje smjesu produkata s niskom regioselektivnošću. Slijedom toga u okviru ovog završnog rada praćena je regioselektivnost N-ferocenoiliranja C-5 derivata uracila uporabom ¹H-NMR spektroskopije. Aciliranje baze provodi se ferocenoil kloridom u acetonitrilu uz deprotonirajući reagens trietilamin, pri čemu kao produkt nastaje smjesa N1- i N1/N3-izomera čiji udio ovisi o samom supstituentu na uracilu. Nucleosides and their analogues play a significant role in drug discovery and development due to their exceptional chemotherapeutic activities, therefore a number of structurally different nucleosides have been synthesized. The presence of multiple nucleophilic sites in nucleobases with similar reactivity in the N-alkylation and N-acylation reaction gives a mixture of products with low regioselectivity. In this thesis the regioselectivity of N-ferrocenoylation of C-5 uracil derivatives was monitored using ¹H-NMR spectroscopy. The acylation of the base is carried out with ferrocenoyl chloride in acetonitrile with the deprotonating reagent triethylamine, and the product is a mixture of N1- and N1/N3-isomers, the proportion of which depends on the substituent on uracil.

Novel symmetrical bis-pyrrolo[2,3-d]pyrimidines and bis-purines and their monomers were synthesized and evaluated for their antiproliferative activity in human lung adenocarcinoma (A549), cervical carcinoma (HeLa), ductal pancreatic adenocarcinoma (CFPAC-1) and metastatic colorectal adenocarcinoma (SW620) cells. The use of ultrasound irradiation as alternative energy input in Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) shortened the reaction time, increased the reaction efficiency and led to the formation of exclusively symmetric bis-heterocycles. DFT calculations showed that triazole formation is exceedingly exergonic and confirmed that the presence of Cu(I) ions is required to overcome high kinetic requirements and allow the reaction to proceed. The influence of various linkers and 6-substituted purine and regioisomeric 7-deazapurine on their cytostatic activity was revealed. Among all the evaluated compounds, the 4-chloropyrrolo[2,3-d]pyrimidine monomer 5f with 4,4′-bis(oxymethylene)biphenyl had the most pronounced, although not selective, growth-inhibitory effect on pancreatic adenocarcinoma (CFPAC-1) cells (IC50 = 0.79 µM). Annexin V assay results revealed that its strong growth inhibitory activity against CFPAC-1 cells could be associated with induction of apoptosis and primary necrosis. Further structural optimization of bis-chloropyrrolo[2,3-d]pyrimidine with aromatic linker is required to develop novel efficient and non-toxic agent against pancreatic cancer.

Cilj ovog rada bila je sinteza novih biološki aktivnih hibrida benzimidazola, pirimidina, 7-deazapurina i 1,2,3-triazola, kao odabranih dušikovih heterocikla. Regioselektivnom 1,3-dipolarnom cikloadicijom azida i alkina uz katalizatore Cu(0), 1M CuSO4 uspješno su sintetizirani ciljani 1,4-disupstituirani 1,2,3-triazolni derivati benzimidazola (1-5), pirimidina (9-17) i 6-klor-7-deazapurina (22). „Click“ reakcije su se odvijale primjenom mikrovalova u smjesi vode i organskih otapala pa možemo zaključiti da su primijenjene sintetske metode prihvatljive za okoliš. Hibridi benzimidazola i 1,2,3-triazola (1-5) pripravljeni su reakcijom kumarinskog azida, aromatskih azida i alkinilnih derivata benzimidazola. N-1,N-3-disupstituirani (9, 11, 13 i 15) i N-1-monosupstituirani (10, 12 i 14) pirimidinski derivati 1,2,3-triazola sintetizirani su reakcijom dipropargilnog derivata pirimidina i aromatskih azida. Potom je provedena Sonogarshira-ina reakcija N-1 triazolnih derivata 5-joduracila (16) i alkina pomoću paladija kao katalizatora, CuI kao ko-katalizator i N,N-dizopropiletilamina kojom su sintetizirani biciklički 6-supstituirani (18b i 19b) i 5,6-disupstituirani furo[2,3-d]pirimidinski (18a i 19a) derivati. „Click“ reakcijom 7-(2-azidoetil)-4-klor-7H-pirolo[2,3-d]pirimidina (21) i 4-kloro-N-(prop-2-inil)benzensulfonamida dobiven je ciljani 1,2,3-triazolni derivat 6-klor-7-deazapurina 22. Strukture svih novopriređenih spojeva potvrđene su spektroskopijom 1H- i 13C-NMR. Antiproliferativna ispitivanja novih spojeva na zloćudne stanice tumora su u tijeku. The aim of this work was the synthesis of new biologically active hybrids of benzimidazole, pyrimidine, 7-deazapurine and 1,2,3-triazole, as selected nitrogen heterocycles. Regioselective 1,3-dipolar cycloaddition of azide and alkyne with Cu(0), 1 M CuSO4 as catalysts were synthesized successfully targeted 1,4-disubstituted 1,2,3-triazole benzimidazole (1-5), pyrimidine (9-17) and 6-chloro-7-deazapurine (22) derivatives. "Click" reactions were conducted by using microwaves in a mixture of water and organic solvents, so we can conclude that the applied synthetic methods were acceptable for the environment. Hybrids of benzimidazole and 1,2,3-triazole (1-5) were prepared by reaction of the coumarin azide, aromatic azide with alkynyl derivatives of benzimidazole. N-1,N-3-disubstituted (9, 11, 13 and 15) and N-1-monosubstituted (10, 12 and 14) pyrimidine derivative of 1,2,3-triazole were synthesized by reaction of a pyrimidine derivatives and aromatic azides. Sonogashira coupling of N-triazole derivative of 5-iodouracil (16) and alkynes using a palladium catalyst, CuI as a co-catalyst and N,N-diisopropylethylamine afforded bicyclic 6-substituted (18b and 19b) and 5,6-disubstituted furo[2,3-d]pyrimidine (18a and 19a) derivatives. "Click" reaction of 7-(2-azidoethyl)-4-chloro-7H-pyrolo[2,3-d]pyrimidine (21) and 4-chloro-N-(prop-2-ynyl)benzenesulfonamide was obtained as a target 1,2,3-triazole derivative of 6-chloro-7-deazapurine 22. The structures of all compounds were confirmed by 1H and 13C NMR spectroscopy. Antiproliferative evaluations of new compounds on malignant tumor cells are in progress.

Cilj ovog rada bila je sinteza i strukturna karakterizacija novih pirimidinskih derivata u svrhu ispitivanja njihovog biološkog djelovanja protiv tumorskih staničnih linija porijeklom iz čovjeka. Reakcijom N-alkiliranja citozina uz prisustvo baze (NaH) kao deprotonirajućeg sredstva i propargil-bromida kao alkilirajućeg reagensa pripravljeni su N-1 propargilirani derivat citozina (1), N,N-1,3-dipropargilirani citozinski derivat (2) te biciklički derivat 3, koji je dobiven 6-endo-dig ciklizacijom monopropargiliranog citozinskog derivata 1. Huisgenovom 1,3-dipolarnom cikloadicijom N,N-1,3-dipropargilcitozina (2) i odgovarajućih azida uz bakar kao katalizator pripravljeni su N-1-triazolil-N-3-propargilni citozinski derivati (6 i 7), te N-1-triazolilni citozinski derivati (4, 5 i 8) pri čemu je uveden 1,2,3-triazolni prsten u položaju N-1 citozina. "Click" reakcijom N,N-1,3-dipropargiliranog citozinskog derivata (2) i 1-azido-4-klorbenzena uz bakar kao katalizator sintetizirani su N-3-triazolilni (8), te N,N-1,3-ditriazolilni citozinski derivat s p-klorfenilnim supstituentom u položaju 4 na 1,2,3-triazolnoj jezgri (9). Strukture novosintetiziranih spojeva potvrđene su 1H NMR spektroskopijom. The aim of this work was the synthes and structural characterization of new pyrimidine derivatives in order to determine their activities against human malignant tumor cell lines. N-1 propargylated cytosine derivative (1), N,N-1,3 dipropargylated cytosine derivative (2) and bicyclic derivative 3 were synthesized by N-alkylation reaction of cytosine using NaH as base and propargyl bromide as alkylating reagent. Bicyclic product 3 was synthesized via 6-endo-dig cyclization reaction of the monopropargylated cytosine derivative 1. Huisgen 1,3-dipolar cycloaddition reaction of N,N-1,3-dipropargylcytosine (2) with corresponding azides, in the presence of copper as a catalyst, gave N-1-triazolyl-N-3-propargylated cytosine derivative (6 and 7), and N-1-triazolyl cytosine derivative (4, 5 and 8) wherein the 1,2,3-triazole ring was introduced into N-1 position of cytosine moiety. "Click" reaction of N,N-1,3-dipropargylated cytosine derivative (2) and 1-azido-4-chlorobenzene with copper as a catalyst gave N-1-triazolyl cytosine derivative (8) and N,N-1,3-ditriazolyl cytosine derivative (9) containing p-chlorophenyl substituent at position 4 on 1,2,3-triazole moiety. The structures of the newly synthesized compounds were confirmed by 1H NMR spectroscopy.

The synthesis of the novel 5-alkyl pyrimidine derivatives, 5, 6-dihydrofuro[2, 3-d]pyrimidines and 5-alkyl N-methoxymethyl pyrimidine derivatives and evaluation of their cytostatic activities are described. The mechanism of antiproliferative effect of 5-(2-chloroethyl)-substituted pyrimidine 3 that exerted the pronounced cytostatic activity was studied in further details on colon carcinoma (HCT116) cells. The cell cycle perturbation analysis demonstrated severe DNA damage (G2/M arrest) pointing to a potential DNA alkylating ability of 3. Preliminary ADME data of 3 and its 6-methylated structural congener (6-Me-3) showed their high permeability and good metabolic stability.