2. Academic Validation
  3. New bioactive 5-arylcarboximidamidopyrazolo[3,4-c]pyridines: Synthesis, cytotoxic activity, mechanistic investigation and structure-activity relationships

New bioactive 5-arylcarboximidamidopyrazolo[3,4-c]pyridines: Synthesis, cytotoxic activity, mechanistic investigation and structure-activity relationships

  • Eur J Med Chem. 2021 Jun 5:218:113387. doi: 10.1016/j.ejmech.2021.113387.
Athanasios Papastathopoulos 1,  Nikolaos Lougiakis 1,  Ioannis K Kostakis 1,  Panagiotis Marakos 2,  Nicole Pouli 1,  Harris Pratsinis 3,  Dimitris Kletsas 3
Affiliations

Affiliations

  • 1 Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771, Athens, Greece.
  • 2 Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771, Athens, Greece. Electronic address: marakos@pharm.uoa.gr.
  • 3 Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, NCSR ''Demokritos'', 15310, Athens, Greece.
PMID: 33774342 DOI: 10.1016/j.ejmech.2021.113387
Abstract

In this study, a series of novel substituted pyrazolo[3,4-c]pyridin-5-ylamidines was synthesized and their cytotoxicity against three Cancer cell lines (MDA-MB-231, HT-1080, PC-3), as well as a human normal cell line (AG01523) was evaluated. A number of derivatives could strongly reduce Cancer cells proliferation and exhibit apoptotic induction capability, while reasonable structure-activity relationships could be extracted. Certain analogues were endowed with low toxicity against normal cells. Cell cycle analysis revealed that most of the active compounds induced a G0/G1 arrest of HT-1080 cells. Moreover, the potential mechanisms of the cytotoxic activity of the promising compounds were investigated in HT-1080 cells, upon study of their effects on the phosphorylation of Akt, ERK and p38 MAPK. Most of the active derivatives inhibit phosphorylation of Akt and ERK and/or induce p38 MAPK phosphorylation, providing a potential indication on the mode of action of this class.

Keywords

Akt; Apoptosis; Cell cycle analysis; Cytotoxicity; ERK; Purine analogues; Pyrazolopyridine; p38 MAPK.

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