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Design and synthesis of new substituted pyrazolopyridines with potent antiproliferative activity

Author(s):

Vassiliki Giannouli, Nikolaos Lougiakis, Ioannis K. Kostakis, Nicole Pouli*, Panagiotis Marakos, Alexios-Leandros Skaltsounis, David A. Horne, Sangkil Nam, Katerina Gioti and Roxane Tenta  

Abstract:


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 properties.

Objectives: Based on previously discovered substituted pyrazolopyridines with promising antiproliferative 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 compounds.

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 antiproliferative 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 pattern, 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.

Keywords:

purine analogues; pyrazolopyridine; carboxamidine; antiproliferative activity; cell cycle effect

Affiliation:

Division of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, Division of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, Division of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, Division of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, Division of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, Division of Pharmacognosy & Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771 , Molecular Medicine, Beckman Research Institute; City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA, 91010, Molecular Medicine, Beckman Research Institute; City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA, 91010, Department of Nutrition & Dietetics, School of Health Sciences and Education, Harokopio University, Athens 17671, Department of Nutrition & Dietetics, School of Health Sciences and Education, Harokopio University, Athens 17671



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