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
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.