当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Novel pyrazolopyridine derivatives as potential angiogenesis inhibitors: Synthesis, biological evaluation and transcriptome-based mechanistic analysis.

Novel pyrazolopyridine derivatives as potential angiogenesis inhibitors: Synthesis, biological evaluation and transcriptome-based mechanistic analysis.

Abstract：

: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 division" along with "cholesterol biosynthesis" as the most significantly altered biological processes.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Michailidou M,Giannouli V,Kotsikoris V,Papadodima O,Kontogianni G,Kostakis IK,Lougiakis N,Chatziioannou A,Kolisis FN,Marakos P,Pouli N,Loutrari H

doi

10.1016/j.ejmech.2016.05.035

subject

Has Abstract

pub_date

2016-10-04 00:00:00

pages

143-157

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(16)30433-0

journal_volume

121

pub_type

杂志文章

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