Synthesis, Cytostatic and Antibacterial Evaluations of Novel 1,2,3-Triazolyl-tagged Pyrimidine and Furo[2,3-d]pyrimidine Derivatives

Maja Stipković Babić,Marijana Jukić,Ana Ratković,Tatjana Gazivoda Kraljević,Ljubica Glavaš-Obrovac,Domagoj Drenjančević,Silvana Raić-Malić

doi:10.5562/cca3165

Maja Stipković Babić, Marijana Jukić + Show 5 more

Open Access

https://doi.org/10.5562/cca3165

Copy DOI

Abstract

C-5 alkynylated and N-1 alkylated pyrimidine derivatives were synthesized by N-alkylation reaction of 5-iodouracil in the presence of NaH, as a base, followed by Pd-catalyzed Sonogashira cross-coupling reaction of N-alkyl-5-iodouracil derivatives (1 and 2) with corresponding terminal alkynes. Intramolecular in situ O- heteroannulation ring closure of N-1- alkyl-C-5- alkynylpyrimidine derivatives (3 and 5) generated novel 6-substituted furo[2, 3-d]pyrimidine derivatives (7 and 8). 1, 4-Disubstituted 1, 2, 3- triazole tethered 5- alkynylpyrimidines (14– 19) and 6-substituted furo[2, 3- d]pyrimidines (20–22) were successfully prepared by the copper(I)- catalyzed click reaction of 5-iodo-N- 1- propargylpyrimidine (2) using microwave irradiation, followed by Sonogashira cross- coupling reaction with corresponding terminal alkynes. In vitro antiproliferative activity of prepared compounds evaluated on human cancer cell lines cervix adenocarcinoma (HeLa), colon adenocarcinoma (CaCo- 2), chronic myeloid leukemia in blast crisis (K562), Burkitt lymphoma (Raji) revealed that pyrimidine (19) and furo[2, 3- d]pyrimidine (22) derivatives with 3, 5- difluorophenyl at pyrimidine and furo[2, 3- d]pyrimidine as well as p- (trifluoromethyl)phenyl at 1, 2, 3-triazole exhibited marked and selective inhibitory effects on the growth of K562 and Raji tumor cells. Antibacterial evaluations showed that pyrimidine derivative 14 substituted with p- tolylethynyl at C-5 of pyrimidine and benzyl at 1, 2, 3-triazole moiety was the most active of all evaluated compounds on the Gram positive bacterial strains Enterococcus faecalis. Further structure optimization of compounds 14, 19 and 22 is foreseen in order to obtain lead structural analogs with efficient and selective antitumoral and antibacterial activities.

Highlights

In continuation of our efforts towards the hybridisation of pyrimidine and 1,2,3triazole scaffolds into a single chemical entity,[25] we report here the synthesis and biological investigations of C-5 alkynylated pyrimidines and C-6-alkylated furo[2,3-d]pyrimidines containing N-1-substituted 1,2,3-triazole ring
Effect of pyrimidine and furo[2,3-d]pyrimidine derivatives of 1,2,3-triazole were investigated on the growth of human cervix adenocarcinoma (HeLa), colon adenocarcinoma (CaCo-2), chronic myeloid leukemia in blast crisis (K562), Burkitt lymphoma (Raji), and on the normal Madin Darby canine kidney (MDCK I) cells as well (Table 1)
Pyrimidine derivatives containing at N-1 buteny substituent (3) and propargyl (4–6) side chain were synthesized by Nalkylation reaction of 5-iodouracil followed by Pd-catalysed Sonogashira cross-coupling reaction of N-alkyl-5-iodouracil derivatives (1 and 2) with corresponding terminal alkynes. 6-Substituted furo[2,3-d]pyrimidine derivatives (7 and 8) were prepared by intramolecular in situ O-hereoannulation ring closure of N-1-alkyl-C-5-alkynylpyrimidine derivatives (3 and 5)

Summary

INTRODUCTION

P YRIMIDINES are essential constituents of all cells and thereby one of the most important heterocyclic compounds.[1,2] pyrimidine based heterocycles are of interest as potential bioactive molecules and posses wide spectrum of biological activities such as anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antitubercular and antimalarial activity.[3,4,5] Modified pyrimidine nucleosides were among the first chemotherapeutic agents to be introduced into the medical treatment of cancer.[6,7] In particular, a number of pyrimidine derivatives with potent biological properties have been prepared by substitution at the 5-position of the pyrimidine ring.[8,9] various five-membered heteroaromatic ringfused pyrimidines are purinomimetics which were subjected to biological investigations to assess their potential therapeutic usefulness such as anti-inflammatory, antibacterial, anticancer and antiviral agents.[10,11,12,13,14,15] furo[2,3d]pyrimidine attract considerable attention due to their great practical significance through exerting pharmacological potential as antiviral, antimicrobial, and antitumor. Agents, and is one of the most recently explored scaffolds to have potential anticancer activity through inhibition of various protein kinases.[16,17,18,19] Besides, it was found that some 1,2,3-triazole tethered pyrimidine nucleosides,[20] 1,2,3-triazole pyrimidine nucleoside conjugates with the 1,2,3-triazole as a substituent at the pyrimidine ring, the sugar moiety or sugar mimic were endowed with a pronounced cytostatic activity.[24] In continuation of our efforts towards the hybridisation of pyrimidine and 1,2,3triazole scaffolds into a single chemical entity,[25] we report here the synthesis and biological investigations of C-5 alkynylated pyrimidines and C-6-alkylated furo[2,3-d]pyrimidines containing N-1-substituted 1,2,3-triazole ring. The effect of substituents at pyrimidine, furo[2,3-d]pyrimidine and 1,2,3-triazole moieties on biological activites was assessed

RESULTS AND DISCUSSION

CONCLUSIONS

General Procedure for Sonogashira Cross-coupling Reaction