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

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Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, HR-10000 Zagreb, Croatia
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Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcet Drive, Cambridge CB3 0AS, UK
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Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička 54, HR-10000 Zagreb, Croatia
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Department of Biotechnology, University of Rijeka, Ulica Radmile Matejčić 2, HR-51000 Rijeka, Croatia
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Faculty of Health Studies, University of Rijeka, Ulica Viktora Cara Emina 5, HR-51000 Rijeka, Croatia
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Faculty of Medicine, Juraj Dobrila University of Pula, HR-52100 Pula, Croatia
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Author to whom correspondence should be addressed.
Academic Editor: Brullo Chiara
Molecules 2021, 26(11), 3334; https://doi.org/10.3390/molecules26113334
Received: 7 May 2021 / Revised: 28 May 2021 / Accepted: 29 May 2021 / Published: 1 June 2021
(This article belongs to the Special Issue Translational Approach to Antitumor Drugs - 2nd Edition)
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. View Full-Text
Keywords: pyrrolo[2,3-d]pyrimidines; purine; DFT calculations; ultrasound; antiproliferative activity; pancreatic adenocarcinoma; apoptosis pyrrolo[2,3-d]pyrimidines; purine; DFT calculations; ultrasound; antiproliferative activity; pancreatic adenocarcinoma; apoptosis
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MDPI and ACS Style

Bistrović Popov, A.; Vianelo, R.; Grbčić, P.; Sedić, M.; Pavelić, S.K.; Pavelić, K.; Raić-Malić, S. Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation. Molecules 2021, 26, 3334. https://doi.org/10.3390/molecules26113334

AMA Style

Bistrović Popov A, Vianelo R, Grbčić P, Sedić M, Pavelić SK, Pavelić K, Raić-Malić S. Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation. Molecules. 2021; 26(11):3334. https://doi.org/10.3390/molecules26113334

Chicago/Turabian Style

Bistrović Popov, Andrea, Robert Vianelo, Petra Grbčić, Mirela Sedić, Sandra K. Pavelić, Krešimir Pavelić, and Silvana Raić-Malić. 2021. "Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation" Molecules 26, no. 11: 3334. https://doi.org/10.3390/molecules26113334

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