- Design and synthesis of new substituted pyrazolopyridines with potent antiproliferative activity
-
Background: Purine isosteres are often endowed with interesting pharmacological properties, due to their involvement in cellular processes replacing the natural purines. Among these compounds, pyrazolopyridines are under active investigation for potential anticancer proper-ties. Objectives: Based on previously discovered substituted pyrazolopyridines with promising antipro-liferative activity, we designed and synthesized new, suitably substituted analogues aiming to investigate their potential activity and contribute to SAR studies of this class of bioactive com-pounds. Methods: The new compounds were synthesized using suitably substituted 2-amino-4-picolines, which upon ring-closure provided substituted pyrazolo[3,4-c] pyridine-5-carbonitriles that served as key intermediates for the preparation of the target 3,5,7 trisubstituted derivatives. The antipro-liferative activity of 31 new target derivatives was evaluated against three cancer cell lines (MIA PaCa-2, PC-3 and SCOV3), whereas cell-cycle perturbations of exponentially growing PC-3 cells, using three selected derivatives were also performed. Results: Eight compounds displayed IC50 values in the low μM range, allowing the extraction of interesting SAR’s. Two of the most potent compounds against all cell lines share a common pat-tern, by accumulating cells at the G0/G1 phase. From this project, a new carboxamidine-substituted hit has emerged. Conclusion: Among the new compounds, those possessing the 3-phenylpyrazolo[3,4-c]pyridine scaffold, proved to be worth investigating and the majority of them showed strong cytotoxic activity against all cell lines, with IC50 values ranging from 0.87-4.3 μM. A carboxamidine analogue that resulted from the synthetic procedure, proved to be highly active against the cancer cells and could be considered as a useful lead for further optimization.
- Giannouli, Vassiliki,Gioti, Katerina,Horne, David A.,Kostakis, Ioannis K.,Lougiakis, Nikolaos,Mara-Kos, Panagiotis,Nam, Sangkil,Pouli, Nicole,Skaltsounis, Alexios-Leandros,Tenta, Roxane
-
p. 176 - 191
(2020/03/10)
-
- Synthesis, docking study and kinase inhibitory activity of a number of new substituted pyrazolo[3,4-c]pyridines
-
A series of new pyrazolo[3,4-c]pyridines bearing various 1, 3, 5 or 1, 3, 7 pattern substitutions, were designed and synthesized. Some of them showed interesting inhibitory activity mainly against glycogen synthase kinase 3 (GSK3)α/β as well as against cdc2-like kinases 1 (CLK1) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), with good selectivity and remarkable structure-activity relationships (SARs), without being cytotoxic. Molecular simulations in correlation with biological data revealed the importance of the existence of N1-H as well as the absence of a bulky 7-substituent.
- Sklepari, Meropi,Lougiakis, Nikolaos,Papastathopoulos, Athanasios,Pouli, Nicole,Marakos, Panagiotis,Myrianthopoulos, Vassilios,Robert, Thomas,Bach, Stéphane,Mikros, Emmanuel,Ruchaud, Sandrine
-
-
- Synthesis and Antiproliferative Activity of New pyrazolo[3,4-c]pyridines
-
Background: Several pyrazolopyridines possess promising pharmacological activities, mainly attributed to their antagonistic nature towards the natural purines in many biological processes. Cytotoxicity and anticancer potential of this class of compounds a
- Gavriil, Efthymios-Spyridon,Lougiakis, Nikolaos,Pouli, Nicole,Marakos, Panagiotis,Skaltsounis, Alexios-Leandros,Nam, Sangkil,Jove, Richard,Horne, David,Gioti, Katerina,Pratsinis, Harris,Kletsas, Dimitris,Tenta, Roxane
-
p. 365 - 374
(2017/06/21)
-
- Pyrazolopyridines. Part 5. Preparation and Reactions of Pyrazolopyridines
-
A series of pyrazolopyridines has been prepared by nitrosation of 3-acetamido-4-methylpyridines and subsequent rearrangement and cyclisation of the N-acetyl-N-nitroso-compounds produced.The reactions of the pyrazolopyridines have been investigated. 1- and 2-Acetyl and 1- and 2-benzyl compounds were obtained and their structures elucidated spectroscopically.The ring system readily undergoes electrophilic substitution in the 3-position. 7-Chloropyrazolopyridine has been shown to be more susceptible to nucleophilic substitution than the isomeric 5-chloro-compound.
- Chapman, David,Hurst, Jim
-
p. 2398 - 2404
(2007/10/02)
-