Περίληψη:
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. © 2020 Bentham Science Publishers.
Συγγραφείς:
Giannouli, V.
Lougiakis, N.
Kostakis, I.K.
Pouli, N.
Mara-Kos, P.
Skaltsounis, A.-L.
Horne, D.A.
Nam, S.
Gioti, K.
Tenta, R.
Λέξεις-κλειδιά:
1 (4 methoxybenzyl) 3 phenyl 7 (phenylamino) 1h pyrazolo[3,4 c]pyridine 5 carbonitrile; 1 (4 methoxybenzyl) 3 phenyl 7 [(3,4,5 trimethoxyphenyl)amino] 1h pyrazolo[3,4 c]pyridine 5 carbonitrile; 3 acetamido 2 chloro 4 methylpyridine 1 oxide; 3 phenyl 5 [[(pyridin 3 ylmethyl)amino]methyl] n (3,4,5 trimethoxyphenyl) 1h pyrazolo[3,4 c]pyridin 7 amine; 3 phenyl 7 (phenylamino) 1h pyrazolo[3,4 c]pyridine 5 carbonitrile; 3 phenyl 7 [(3,4,5 trimethoxyphenyl)amino] 1h pyrazolo[ 3,4 c]pyridine 5 carbonitrile; 5 (aminomethyl) 3 phenyl n (3,4,5 trimethoxyphenyl) 1h pyrazolo[3,4 c]pyridin 7 amine; 5 (aminomethyl) n (3,4,5 trimethoxyphenyl) 1h pyrazolo[ 3,4 c]pyridin 7 amine; 5 (aminomethyl) n phenyl 1h pyrazolo[3,4 c]pyridin 7 amine; 5 (aminomethyl) n,3 diphenyl 1h pyrazolo[3,4 c]pyridin 7 amine; 5 [(benzylamino)methyl] 3 phenyl n (3,4,5 trimethoxyphenyl) 1h pyrazolo[3,4 c]pyridin 7 amine; 5 [(benzylamino)methyl] n (3,4,5 trimethoxyphenyl) 1h pyrazolo[3,4 c]pyridin 7 amine; 5 [(benzylamino)methyl] n phenyl 1h pyrazolo[3,4 c]pyridin 7 amine; 5 [(benzylamino)methyl] n,3 diphenyl 1h pyrazolo [3,4 c]pyridin 7 amine; 5 [[(1 methylpiperidin 4 yl)amino]methyl] n (3,4, 5 trimethoxyphenyl) 1h pyrazolo[3,4 c]pyridin 7 amine; 5 [[(1 methylpiperidin 4 yl)amino]methyl] n phenyl 1h pyrazolo[3,4 c]pyridin 7 amine; 5 [[(1 methylpiperidin 4 yl)amino]methyl] n,3 diphenyl 1h pyrazolo[3,4 c]pyridin 7 amine; 5 [[(pyridin 3 yl methyl)amino]methyl] n (3,4,5 trimethoxyphenyl) 1h pyrazolo[3,4 c]pyridin 7 amine; 7 (phenylamino) 1h pyrazolo[3,4 c]pyridine 5 carbonitrile; 7 chloro 1h pyrazolo[3,4 c]pyridine 5 carbonitrile; 7 chloro 3 iodo 1h pyrazolo[3,4 c]pyridine 5 carbonitrile; 7 chloro 3 phenyl 1h pyrazolo[3,4 c]pyridine 5 carbonitrile; 7 [(3,4,5 trimethoxyphenyl)amino] 1h pyrazolo[3,4 c]pyridine 5 carbonitrile; antineoplastic agent; n (2 chloro 6 cyano 4 methylpyridin 3 yl)acetamide; n ,3 diphenyl 7 (phenylamino) 1h pyrazolo[3,4 c]pyridine 5 carboximidamide; n phenyl 5 [[(pyridin 3 ylmethyl)amino]methyl] 1h pyrazolo[3,4 c]pyridin 7 amine; n,3 diphenyl 5 [[(pyridin 3 ylmethyl)amino]methyl] 1h pyrazolo[3,4 c]pyridin 7 amine; pyrazolopyrimidine derivative; unclassified drug; unindexed drug; antineoplastic agent; pyridine derivative, A2058 cell line; antineoplastic activity; antiproliferative activity; apoptosis; Article; cell cycle S phase; comparative study; controlled study; cytotoxicity; drug design; drug potency; drug screening; drug synthesis; DU145 cell line; flow cytometry; G2 phase cell cycle checkpoint; heteronuclear multiple bond correlation; heteronuclear multiple quantum coherence; human; human cell; melting point; MIA PaCa-2 cell line; nuclear Overhauser effect; PC-3 [Human prostate carcinoma] cell line; percentage of cells in G0/G1 phase; priority journal; proton nuclear magnetic resonance; reaction analysis; structure activity relation; cell cycle; cell proliferation; cell survival; chemistry; drug effect; synthesis; tumor cell line, Antineoplastic Agents; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemistry Techniques, Synthetic; Drug Design; Humans; Pyridines
