Novel Bis- and Mono-Pyrrolo[2,3-<i>d</i>]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation
Novel symmetrical bis-pyrrolo[2,3-<i>d</i>]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 colorect...
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MDPI AG
2021-06-01
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| Online Access: | https://www.mdpi.com/1420-3049/26/11/3334 |
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| author | Andrea Bistrović Popov Robert Vianelo Petra Grbčić Mirela Sedić Sandra Kraljević Pavelić Krešimir Pavelić Silvana Raić-Malić |
| author_facet | Andrea Bistrović Popov Robert Vianelo Petra Grbčić Mirela Sedić Sandra Kraljević Pavelić Krešimir Pavelić Silvana Raić-Malić |
| author_sort | Andrea Bistrović Popov |
| collection | DOAJ |
| description | Novel symmetrical bis-pyrrolo[2,3-<i>d</i>]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-<i>d</i>]pyrimidine monomer <b>5f</b> with 4,4′-bis(oxymethylene)biphenyl had the most pronounced, although not selective, growth-inhibitory effect on pancreatic adenocarcinoma (CFPAC-1) cells (IC<sub>50</sub> = 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-<i>d</i>]pyrimidine with aromatic linker is required to develop novel efficient and non-toxic agent against pancreatic cancer. |
| first_indexed | 2024-03-10T10:48:06Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T10:48:06Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-befb393670054d2cbc6c8a3199017e8c2023-11-21T22:27:19ZengMDPI AGMolecules1420-30492021-06-012611333410.3390/molecules26113334Novel Bis- and Mono-Pyrrolo[2,3-<i>d</i>]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative EvaluationAndrea Bistrović Popov0Robert Vianelo1Petra Grbčić2Mirela Sedić3Sandra Kraljević Pavelić4Krešimir Pavelić5Silvana Raić-Malić6Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, HR-10000 Zagreb, CroatiaDivision of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička 54, HR-10000 Zagreb, CroatiaDepartment of Biotechnology, University of Rijeka, Ulica Radmile Matejčić 2, HR-51000 Rijeka, CroatiaDepartment of Biotechnology, University of Rijeka, Ulica Radmile Matejčić 2, HR-51000 Rijeka, CroatiaFaculty of Health Studies, University of Rijeka, Ulica Viktora Cara Emina 5, HR-51000 Rijeka, CroatiaFaculty of Medicine, Juraj Dobrila University of Pula, HR-52100 Pula, CroatiaDepartment of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, HR-10000 Zagreb, CroatiaNovel symmetrical bis-pyrrolo[2,3-<i>d</i>]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-<i>d</i>]pyrimidine monomer <b>5f</b> with 4,4′-bis(oxymethylene)biphenyl had the most pronounced, although not selective, growth-inhibitory effect on pancreatic adenocarcinoma (CFPAC-1) cells (IC<sub>50</sub> = 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-<i>d</i>]pyrimidine with aromatic linker is required to develop novel efficient and non-toxic agent against pancreatic cancer.https://www.mdpi.com/1420-3049/26/11/3334pyrrolo[2,3-<i>d</i>]pyrimidinespurineDFT calculationsultrasoundantiproliferative activitypancreatic adenocarcinoma |
| spellingShingle | Andrea Bistrović Popov Robert Vianelo Petra Grbčić Mirela Sedić Sandra Kraljević Pavelić Krešimir Pavelić Silvana Raić-Malić Novel Bis- and Mono-Pyrrolo[2,3-<i>d</i>]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation Molecules pyrrolo[2,3-<i>d</i>]pyrimidines purine DFT calculations ultrasound antiproliferative activity pancreatic adenocarcinoma |
| title | Novel Bis- and Mono-Pyrrolo[2,3-<i>d</i>]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation |
| title_full | Novel Bis- and Mono-Pyrrolo[2,3-<i>d</i>]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation |
| title_fullStr | Novel Bis- and Mono-Pyrrolo[2,3-<i>d</i>]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation |
| title_full_unstemmed | Novel Bis- and Mono-Pyrrolo[2,3-<i>d</i>]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation |
| title_short | Novel Bis- and Mono-Pyrrolo[2,3-<i>d</i>]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation |
| title_sort | novel bis and mono pyrrolo 2 3 i d i pyrimidine and purine derivatives synthesis computational analysis and antiproliferative evaluation |
| topic | pyrrolo[2,3-<i>d</i>]pyrimidines purine DFT calculations ultrasound antiproliferative activity pancreatic adenocarcinoma |
| url | https://www.mdpi.com/1420-3049/26/11/3334 |
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