1. Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation
- Author
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Mirela Sedić, Krešimir Pavelić, Sandra Kraljević Pavelić, Andrea Bistrovic Popov, Petra Grbčić, Robert Vianelo, Silvana Raić-Malić, Vianelo, Robert [0000-0003-1779-4524], Grbčić, Petra [0000-0002-5711-6237], Sedić, Mirela [0000-0003-4679-1541], Pavelić, Sandra Kraljević [0000-0003-0491-673X], Pavelić, Krešimir [0000-0001-7706-6858], Raić-Malić, Silvana [0000-0001-5021-8970], and Apollo - University of Cambridge Repository
- Subjects
Purine ,Pharmaceutical Science ,DFT calculations ,01 natural sciences ,7. Clean energy ,Analytical Chemistry ,HeLa ,chemistry.chemical_compound ,QD241-441 ,0302 clinical medicine ,pyrrolo[2, 3‐d]pyrimidines ,purine ,ultrasound ,antiproliferative activity ,pancreatic adenocarcinoma ,apoptosis ,Drug Discovery ,Density Functional Theory ,Cycloaddition Reaction ,biology ,Chemistry ,Cycloaddition ,3. Good health ,Chemistry (miscellaneous) ,030220 oncology & carcinogenesis ,Molecular Medicine ,Adenocarcinoma ,Pyrimidine ,Cell Survival ,Stereochemistry ,Triazole ,Antineoplastic Agents ,pyrrolo[2,3-d]pyrimidines ,Article ,03 medical and health sciences ,Cell Line, Tumor ,Pancreatic cancer ,medicine ,Humans ,Pyrroles ,Physical and Theoretical Chemistry ,Cell Proliferation ,010405 organic chemistry ,Organic Chemistry ,medicine.disease ,biology.organism_classification ,0104 chemical sciences ,Pyrimidines ,A549 Cells ,Drug Screening Assays, Antitumor ,Linker ,HeLa Cells - Abstract
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.
- Published
- 2021