Τίτλος:
Synthesis and Antiproliferative Activity of New pyrazolo[3,4-c]pyridines
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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 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. © 2017 Bentham Science Publishers.
Συγγραφείς:
Gavriil, E.-S.
Lougiakis, N.
Pouli, N.
Marakos, P.
Skaltsounis, A.-L.
Nam, S.
Jove, R.
Horne, D.
Gioti, K.
Pratsinis, H.
Kletsas, D.
Tenta, R.
Περιοδικό:
RSC Medicinal Chemistry
Εκδότης:
Bentham Science Publishers B.V.
Λέξεις-κλειδιά:
1 (4 methoxybenzyl) 3 (pyridin 3 yl) 7 (pyrrolidin 1 yl) 1h pyrazolo[3,4 c]pyridine; 1 (4 methoxybenzyl) 7 (4 methylpiperazin 1 yl) 3 (pyridin 3 yl) 1h pyrazolo[3,4 c]pyridine; 1 (4 methoxybenzyl) 7 (morpholin 4 yl) 3 (pyridin 3 yl) 1h pyrazolo[3,4 c]pyridine; 3 (3 fluorophenyl) 1 (4 methoxybenzyl) 7 (4 methylpiperazin 1 yl) 1h pyrazolo[3,4 c]pyridine; 3 (3 fluorophenyl) 1 (4 methoxybenzyl) 7 (morpholin 4 yl) 1h pyrazolo[3,4 c]pyridine; 3 (3 fluorophenyl) 1 (4 methoxybenzyl) 7 (pyrrolidin 1 yl) 1h pyrazolo[3,4 c]pyridine; 3 (3 fluorophenyl) 7 (4 methylpiperazin 1 yl) 1h pyrazolo[3,4 c]pyridine; 3 (3 fluorophenyl) 7 (morpholin 4 yl) 1h pyrazolo[3,4 c]pyridine; 3 (3 fluorophenyl) 7 (pyrrolidin 1 yl) 1h pyrazolo[3,4 c]pyridine; 3 (pyridin 3 yl) 7 (pyrrolidin 1 yl) 1h pyrazolo[3,4 c]pyridine; 3,7 bis(3 fluorophenyl) 1 (4methoxybenzyl) 1h pyrazolo[3,4 c]pyridine; 3,7 bis(3 fluorophenyl) 1h pyrazolo[3,4 c]pyridine; 7 (4 methylpiperazin 1 yl) 3 (pyridin 3 yl) 1h pyrazolo[3,4 c]pyridine; 7 (morpholin 4 yl) 3 (pyridin 3 yl) 1h pyrazolo[3,4 c]pyridine; 7 chloro 1 (4 methoxybenzyl) 3 (pyridin 3 yl) 1h pyrazolo[3,4 c]pyridine; 7 chloro 3 (3 fluorophenyl) 1 (4 methoxybenzyl) 1h pyrazolo[3,4 c]pyridine; 7 chloro 3 iodo 1 (4 methoxybenzyl) 1h pyrazolo[3,4 c]pyridine; 7 chloro 3 iodo 1h pyrazolo[3,4 c]pyridine; 7 chloro 3 iodo 2 (4 methoxybenzyl) 2h pyrazolo[3,4 c]pyridine; 7 dimethylamino 1 (4 methoxybenzyl) 3 (pyridin 3 yl) 1h pyrazolo[3,4 c]pyridine; 7 dimethylamino 3 (3 fluorophenyl) 1 (4 methoxybenzyl) 1h pyrazolo[3,4 c]pyridine; 7 dimethylamino 3 (3 fluorophenyl) 1h pyrazolo[3,4 c]pyridine; 7 dimethylamino 3 (pyridin 3 yl) 1h pyrazolo[3,4 c]pyridine; cytotoxic agent; pyrazole derivative; pyridine derivative; unclassified drug, antiproliferative activity; apoptosis; Article; cancer cell line; carbon nuclear magnetic resonance; cell cycle phase; cell cycle S phase; cell death; cell proliferation; cell viability; chromatography; controlled study; DNA content; drug cytotoxicity; drug design; drug synthesis; flow cytometry; heteronuclear multiple bond correlation; heteronuclear multiple quantum coherence; human; human cell; IC50; male; melanoma; nuclear Overhauser effect; nucleophilicity; priority journal; prostate cancer cell line; proton nuclear magnetic resonance; Suzuki reaction
DOI:
10.2174/1573406412666161213124450
