Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

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

Volume 16, Issue 2, 2020

Page: [176 - 191] Pages: 16

DOI: 10.2174/1573406415666190222130225

Price: $65

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: Antiproliferative activity, purine analogues, pyrazolopyridine, carboxamidine, antiproliferative activity, cell cycle effect.

« Previous Next »
Graphical Abstract

[1]
Taieb, J.; Pointet, A-L.; Van Laethem, J.L.; Laquente, B.; Pernot, S.; Lordick, F.; Reni, M. What treatment in 2017 for inoperable pancreatic cancers? Ann. Oncol., 2017, 28, 1473-1483.
[2]
Neoptolemos, J.P.; Kleeff, J.; Costello, P.M.E.; Greenhalf, W.; Palmer, D.H. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat. Rev. Gastroenterol. Hepatol., 2018, 15, 333-348.
[3]
Ducray, R.; Ballard, P.; Barlaam, B.C.; Hickinson, M.D.; Kettle, J.G.; Ogilvie, D.J.; Trigwell, C.B. Novel 3-alkoxy-1H-pyrazolo[3,4-d]pyrimidines as EGFR and erbB2 receptor tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett., 2008, 18, 959-962.
[4]
Baviskar, A.T.; Banerjee, U.C.; Gupta, M.; Singh, R.; Kumar, S.; Gupta, M.K.; Kumar, S.; Raut, S.K.; Khullar, M.; Singh, S.; Kumar, R. Synthesis of imine-pyrazolopyrimidinones and their mechanistic interventions on anticancer activity. Bioorg. Med. Chem., 2013, 21, 5782-5793.
[5]
Park, H-K.; Jeong, H.; Ko, E.; Lee, G.; Lee, J-E.; Lee, S.K.; Lee, A-J. Im, J.Y.; Hu, S.; Kim, S.H.; Lee, J.H.; Lee, C.; Kang, S.; Kang, B.H. Paralog Specificity Determines Subcellular Distribution, Action Mechanism, and Anticancer Activity of TRAP1 Inhibitors. J. Med. Chem., 2017, 60, 7569-7578.
[6]
Bakavoli, M.; Bagherzadeh, G.; Vaseghifar, M.; Shiri, A.; Pordel, M.; Mashreghi, M.; Pordeli, P.; Araghi, M. Molecular iodine promoted synthesis of new pyrazolo[3,4-d]pyrimidine derivatives as potential antibacterial agents. Eur. J. Med. Chem., 2010, 45, 647-650.
[7]
Curran, K.J.; Verheijen, J.C.; Kaplan, J.; Richard, D.J.; Toral-Barza, L.; Hollander, I.; Lucas, J.; Ayral-Kaloustian, S.; Yu, K.; Zask, A. Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 1-substituent. Bioorg. Med. Chem. Lett., 2010, 20, 1440-1444.
[8]
Kim, I.; Song, J.H.; Park, C.M.; Jeong, J.W.; Kim, H.R.; Ha, J.R.; No, Z.; Hyun, Y.L.; Cho, Y.S.; Kang, N.S.; Jeon, D.J. Design, synthesis, and evaluation of 2-aryl-7-(3′,4′-dialkoxyphenyl)-pyrazolo[1,5-a]pyrimidines as novel PDE-4 inhibitors. Bioorg. Med. Chem. Lett., 2010, 20, 922-926.
[9]
El-Kalyoubi, S.A. Synthesis and anticancer evaluation of some novel pyrimido[5,4-e][1,2,4]triazines and pyrazolo[3,4-d]pyri-midine using DMF-DMA as methylating and cyclizing agent. Chem. Cent. J., 2018, 12, 64-78.
[10]
Radi, M.; Dreassi, E.; Brullo, C.; Crespan, E.; Tintori, C.; Bernardo, V.; Valoti, M.; Zamperini, C.; Daigl, H.; Musumeci, F.; Carraro, F.; Naldini, A.; Filippi, I.; Maga, G.; Schenone, S.; Botta, M. Design, synthesis, biological activity, and ADME properties of pyrazolo[3,4-d]pyrimidines active in hypoxic human leukemia cells: a lead optimization study. J. Med. Chem., 2011, 58, 2610-2626.
[11]
Bharate, S.B.; Mahajan, T.R.; Gole, Y.R.; Nambiar, M.; Matan, T.T.; Kulkarni-lmeida, A.; Balachandran, S.; Junjappa, H.; Balakrishnan, A.; Vishwakarma, R.A. Synthesis and evaluation of pyrazolo[3,4-b]pyridines and its structural analogues as TNF-alpha and IL-6 inhibitors. Bioorg. Med. Chem., 2008, 16, 7167-7176.
[12]
Park, C.M.; Jadhav, V.B.; Song, J-H.; Won, H.Y.; Choi, S.U. 3-Amino-1H-pyrazolopyridine derivatives as a maternal embryonic leucine zipper kinase inhibitor. Bull. Korean Chem. Soc., 2017, 38, 595-602.
[13]
Lin, R.; Connolly, P.J.; Lu, Y.; Chiu, G.; Li, S.; Yu, Y.; Huang, S.; Li, X.; Emanuel, S.L.; Middleton, S.A.; Gruninger, R.H.; Adams, M.; Fuentes-Pesquera, A.R.; Greenberger, L.M. Synthesis and evaluation of pyrazolo[3,4-b]pyridine CDK1 inhibitors as anti-tumor agents. Bioorg. Med. Chem. Lett., 2007, 17, 4297-4302.
[14]
Wang, X.; Kolesnikov, A.; Tay, S.; Chan, G.; Chao, Q.; Do, S.; Drummond, J.; Ebens, A.J.; Liu, N.; Ly, J.; Harstad, E.; Hu, H.; Moffat, J.; Munugalavadla, V.; Murray, J.; Slaga, D.; Tsui, V.; Vol-Volgraf, M.; Wallweber, H.; Chang, J.H. Discovery of 5-azaindazole (GNE-955) as a potent pan-pim inhibitor with optimized bioavailability. J. Med. Chem., 2017, 60, 4458-4473.
[15]
Tucker, T.J.; Sisko, J.T.; Tynebor, R.M.; Williams, T.M.; Felock, P.J.; Flynn, J.A.; Lai, M.T.; Liang, Y.; McGaughey, G.; Liu, M.; Miller, M.; Moyer, G.; Munshi, V.; Perlow-Poehnelt, R.; Prasad, S.; Reid, J.C.; Sanchez, R.; Torrent, M.; Vacca, J.P.; Wan, B.L.; Yan, Y.J. Discovery of 3-5-[(6-Amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy-5-chlorobenzonitrile (MK-4965): A Potent, Orally Bioavailable HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor with Improved Potency against Key Mutant Viruses. Med. Chem., 2008, 51, 6503-6511.
[16]
Michailidou, M.; Giannouli, V.; Kotsikoris, V.; Papadodima, O.; Kontogianni, G.; Kostakis, I.K.; Lougiakis, N.; Chatziioannou, A.; Kolisis, F.N.; Marakos, P.; Pouli, N.; Loutrari, H. Novel pyrazolopyridine derivatives as potential angiogenesis inhibitors: Synthesis, biological evaluation and transcriptome-based mechanistic analysis. Eur. J. Med. Chem., 2016, 121, 143-157.
[17]
Sklepari, M.; Lougiakis, N.; Papastathopoulos, A.; Pouli, N.; Marakos, P.; Myrianthopoulos, V.; Robert, T.; Bach, S.; Mikros, E.; Ruchau, S. Synthesis, docking study and kinase inhibitory activity of a number of new substituted pyrazolo[3,4-c]pyridines. Chem. Pharm. Bull., 2017, 65, 66-81.
[18]
Daniilides, K.; Lougiakis, N.; Evangelidis, T.; Kostakis, I.K.; Pouli, N.; Marakos, P.; Mikros, E.; Skaltsounis, A.L.; Bach, S.; Baratte, B.; Ruchaud, S.; Karamani, V.; Papafotika, A.; Christoforidis, S.; Argyros, O.; Kouvari, E.; Tamvakopoulos, C. Discovery of new aminosubstituted pyrrolopyrimidines with antiproliferative activity against breast cancer cells and investigation of their effect towards the PI3Kα enzyme. Anticancer. Agents Med. Chem., 2017, 17, 990-1002.
[19]
Argyros, O.; Lougiakis, N.; Kouvari, E.; Papafotika, A.; Raptopoulou, C.P.; Psycharis, V.; Christoforidis, S.; Pouli, N.; Marakos, P.; Tamvakopoulos, C. Design and synthesis of novel 7-aminosubstituted pyrido[2,3-b]pyrazines exhibiting anti-breast cancer activity. Eur. J. Med. Chem., 2017, 126, 954-968.
[20]
Giannouli, V.; Lougiakis, N.; Kostakis, I.K.; Pouli, N.; Marakos, P.; Skaltsounis, A.L.; Nam, S.; Jove, R.; Horne, D.; Tenta, R.; Pratsinis, H.; Kletsas, D. The discovery of new cytotoxic pyrazolopyridine derivatives. Bioorg. Med. Chem. Lett., 2016, 26, 5229-5233.
[21]
Pino, L.N.; Zehrung, W.S. III. Preparation of pure 2-aminonitro-pyridines and 2-aminonitropicolines. rapid separations by sublimation. J. Am. Chem. Soc., 1955, 77, 3154-3155.
[22]
Brown, E.V. Syntheses and decarboxylation of the isomeric nitropyridinecarboxylic acids. J. Am. Chem. Soc., 1954, 74, 3167-3168.
[23]
Kourafalos, V.N.; Marakos, P.; Pouli, N.; Terzis, A.; Townsend, L.B. Synthesis of 7-aminopyrazolo[3,4-c]pyridine as a probe for the preparation of compounds of pharmacological interest. Heterocycles, 2002, 57, 2335-2344.
[24]
Jin, F.; Confalone, P.N. Palladium-catalyzed cyanation reactions of aryl chlorides. Tetrahedron Lett., 2000, 41, 3271-3273.
[25]
Anbarasan, P.; Schareina, T.; Beller, M. Recent developments and perspectives in palladium-catalyzed cyanation of aryl halides: synthesis of benzonitriles. Chem. Soc. Rev., 2011, 40, 5049-5067.
[26]
Vistica, D.T.; Skehan, P.; Scudiero, D.; Monks, A.; Pittman, A.; Boyd, M.R. Tetrazolium-based assays for cellular viability: a critical examination of selected parameters affecting formazan production. Cancer Res., 1991, 51, 2515-2520.

Rights & Permissions Print Cite
Article Metrics
37
1
© 2024 Bentham Science Publishers | Privacy Policy