Τίτλος:
Novel pyrazolopyridine derivatives as potential angiogenesis inhibitors: Synthesis, biological evaluation and transcriptome-based mechanistic analysis
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Modified purine derivatives exemplified by pyrazolopyrimidines have emerged as highly selective inhibitors of several angiogenic receptor tyrosine kinases. Herein, we designed and synthesized a new series of substituted pyrazolopyridines and explored their ability to influence crucial pro-angiogenic attributes of endothelial cells. Four of the synthesized compounds, possessing analogous substitution pattern, were found able to inhibit at low micromolar concentrations endothelial cell proliferation, migration and differentiation, constitutively or in response to Vascular Endothelial Growth Factor (VEGF) and to attenuate VEGF-induced phosphorylation of VEGF receptor-2 and downstream kinases AKT and ERK1/2. Administration of effective compounds in mice delayed the growth of syngeneic Lewis lung carcinoma transplants and reduced tumor microvessel density, without causing toxicity. Genome-wide microarray and gene ontology analyses of treated endothelial cells revealed derivative 18c as the most efficient modulator of gene expression and mitotic cell cycle/cell divisiong along with ĝ cholesterol biosynthesisĝ as the most significantly altered biological processes. © 2016 Elsevier Masson SAS.
Συγγραφείς:
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.
Περιοδικό:
European Journal of Medicinal Chemistry
Εκδότης:
Elsevier Masson s.r.l.
Λέξεις-κλειδιά:
1 (4 methoxybenzyl) 7 (4 methylpiperazin 1 yl) n phenyl 1h pyrazolo[3,4 c]pyridin 5 amine; 1 (4 methoxybenzyl) 7 (4 methylpiperazin 1 yl) n [4 (4 methylpiperazin 1 yl)phenyl] 1h pyrazolo[3,4 c]pyridin 5 amine; 1 (4 methoxybenzyl) 7 (4 methylpiperazin 1 yl) n [4 (4 methylpiperazin 1 yl)phenyl] 3 phenyl 1h pyrazolo[3,4 c]pyridin 5 amine; 1 (4 methoxybenzyl) n [4 (4 methylpiperazin 1 yl)phenyl] 3 phenyl 7 (piperazin 1 yl) 1h pyrazolo[3,4 c]pyridin 5 amine; 1 (4 methoxybenzyl) n [4 (4 methylpiperazin 1 yl)phenyl] 7 (pyrrolidin 1 yl) 1h pyrazolo[3,4 c]pyridin 5 amine; 1 (4 methoxybenzyl) n,3 diphenyl 7 (piperazin 1 yl) 1h pyrazolo[3,4 c]pyridin 5 amine; 5 chloro 1 (4 methoxybenzyl) 1h pyrazolo[3,4 c]pyridine; 5 chloro 1 (4 methoxybenzyl) 1h pyrazolo[3,4 c]pyridine 6 oxide; 5 chloro 1 (4 methoxybenzyl) 3 phenyl 1h pyrazolo[3,4 c]pyridine; 5 chloro 1 (4 methoxybenzyl) 3 phenyl 1h pyrazolo[3,4 c]pyridine 6 oxide; 5 chloro 1 (4 methoxybenzyl) 3 phenyl 7 (4 methylpiperazin 1 yl) 1h pyrazolo[3,4 c]pyridine; 5 chloro 1 (4 methoxybenzyl) 3 phenyl 7 (piperazin 1 yl) 1h pyrazolo[3,4 c]pyridine; 5 chloro 1 (4 methoxybenzyl) 7 (4 methylpiperazin 1 yl) 1h pyrazolo[3,4 c]pyridine; 5 chloro 1 (4 methoxybenzyl) 7 (piperazin 1 yl) 1h pyrazolo[3,4 c]pyridine; 5 chloro 1 (4 methoxybenzyl) 7 (pyrrolidin 1 yl) 1h pyrazolo[3,4 c]pyridine; 5,7 dichloro 1 (4 methoxybenzyl) 1h pyrazolo[3,4 c]pyridine; 5,7 dichloro 1 (4 methoxybenzyl) 3 phenyl 1h pyrazolo[3,4 c]pyridine; angiogenesis inhibitor; mitogen activated protein kinase 1; mitogen activated protein kinase 3; pyrazolopyridine derivative; pyridine derivative; unclassified drug; vasculotropin receptor 2; angiogenesis inhibitor; pyrazole derivative; pyrazolopyridine; pyridine derivative; transcriptome; vasculotropin A, animal experiment; antiangiogenic activity; Article; cancer growth; capillary density; carbon nuclear magnetic resonance; cell differentiation; cell migration; cell proliferation; cholesterol synthesis; controlled study; drug design; drug screening; drug synthesis; endothelium cell; gene expression; gene ontology; human; human cell; Lewis carcinoma; Lewis lung carcinoma cell; mitosis; mouse; nonhuman; protein phosphorylation; proton nuclear magnetic resonance; transcriptomics; tumor volume; Western blotting; animal; Carcinoma, Lewis Lung; chemistry; drug effects; drug screening; Neovascularization, Pathologic; synthesis, Angiogenesis Inhibitors; Animals; Carcinoma, Lewis Lung; Drug Design; Endothelial Cells; Humans; Mice; Neovascularization, Pathologic; Pyrazoles; Pyridines; Transcriptome; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays
DOI:
10.1016/j.ejmech.2016.05.035
