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Synthesis and Antiproliferative Activity of New pyrazolo[3,4-c]pyridines

[ Vol. 13 , Issue. 4 ]

Author(s):

Efthymios-Spyridon Gavriil, Nikolaos Lougiakis, Nicole Pouli, Panagiotis Marakos, Alexios-Leandros Skaltsounis, Sangkil Nam, Richard Jove, David Horne, Katerina Gioti, Harris Pratsinis, Dimitris Kletsas and Roxane Tenta   Pages 365 - 374 ( 10 )

Abstract:


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 are mainly related to induction of apoptotic cell death and inhibition of protein kinases.

Objectives: This prompted us to design, synthesize and study the antiproliferative activity of a number of new 3,7-disubstituted pyrazolo[3,4-c] pyridines.

Methods: 2-amino-3-nitro-4-picoline was suitably modified and ring closed to provide 7-chloropyrazolo[ 3,4-c]pyridine. Iodination of this derivative was followed by the insertion of 3-aryl substituents via Suzuki coupling and aromatic nucleophilic substitution of the 7-chloro group by the appropriate amines. The antiproliferative activity of the target compounds was evaluated against A2058 melanoma, DU145 and PC3 prostate cancer cell lines. Flow cytometric analysis of DNA content for selected compounds was performed, after incubation of exponentially growing PC-3 cells.

Results: Eighteen new pyrazolopyridines have been synthesized and fully characterized. Among them, the majority of the 3-(3-fluorophenyl) derivatives exhibit interesting antiproliferative activity, with IC50 values in the range of 3.0-16.0 µ M and present reasonable SARs. Cell-cycle perturbations revealed that the most active derivative 12a blocks cells at the S phase.

Conclusion: 3-(3-Fluorophenyl)-7-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-c]pyridine (12a) and the corresponding 1-(4-methoxybenzyl)- analogue (11a) possess interesting antiproliferative activity against all cell lines tested. Derivatives bearing this substitution pattern can be considered as useful leads for further biological evaluation.

Keywords:

Apoptosis, cell cycle selectivity, cell viability, cytotoxicity, purine analogues, pyrazolopyridine.

Affiliation:

School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, School of Health Sciences, Department of Pharmacy, Division of Pharmacognosy & Natural Products Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens 15771, Beckman Research Institute, Comprehensive Cancer Center City of Hope, Los Angeles, NSU Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL, Beckman Research Institute, Comprehensive Cancer Center City of Hope, Los Angeles, Department of Science of Nutrition-Dietetics, Harokopio University, 70 El. Venizelou Street, Athens 17671, Laboratory of Cell Proliferation and Ageing, Institute of Biosciences & Applications, NCSR , Laboratory of Cell Proliferation and Ageing, Institute of Biosciences & Applications, NCSR , Department of Science of Nutrition-Dietetics, Harokopio University, 70 El. Venizelou Street, Athens 17671

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