Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation

Molecules

Petra Grbčić¹  Mirela Sedić¹  Silvana Raić-Malić²  Andrea Bistrović Popov²  Robert Vianelo³  Sandra Kraljević Pavelić⁴  Krešimir Pavelić⁵ 

[1] Department of Biotechnology, University of Rijeka, Ulica Radmile Matejčić 2, HR-51000 Rijeka, Croatia;Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, HR-10000 Zagreb, Croatia;Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička 54, HR-10000 Zagreb, Croatia;Faculty of Health Studies, University of Rijeka, Ulica Viktora Cara Emina 5, HR-51000 Rijeka, Croatia;Faculty of Medicine, Juraj Dobrila University of Pula, HR-52100 Pula, Croatia;

关键词: pyrrolo[2,3-d]pyrimidines;    purine;    DFT calculations;    ultrasound;    antiproliferative activity;    pancreatic adenocarcinoma;   

DOI  :  10.3390/molecules26113334

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown