title: 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.
authors.affiliation: GP Livanos and M Simou Laboratories, 1st Department of Critical Care Medicine & Pulmonary Services, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, 3 Ploutarchou St., 106 75, Athens, Greece. Electronic address: mmichail@med.uoa.gr.
authors.forename: Maria
authors.initials: M
authors.lastname: Michailidou
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens, 15771, Greece. Electronic address: v_giannouli@yahoo.gr.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Giannouli
authors.affiliation: GP Livanos and M Simou Laboratories, 1st Department of Critical Care Medicine & Pulmonary Services, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, 3 Ploutarchou St., 106 75, Athens, Greece. Electronic address: vasiliskotsikoris@yahoo.gr.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Kotsikoris
authors.affiliation: Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Ave., 116 35, Athens, Greece. Electronic address: opapadod@eie.gr.
authors.forename: Olga
authors.initials: O
authors.lastname: Papadodima
authors.affiliation: Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Ave., 116 35, Athens, Greece. Electronic address: gkontogianni@eie.gr.
authors.forename: Georgia
authors.initials: G
authors.lastname: Kontogianni
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens, 15771, Greece. Electronic address: ikkostakis@pharm.uoa.gr.
authors.forename: Ioannis K
authors.initials: IK
authors.lastname: Kostakis
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens, 15771, Greece. Electronic address: nlougiak@pharm.uoa.gr.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Lougiakis
authors.affiliation: Metabolic Engineering and Bioinformatics Group, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vassileos Constantinou Ave., 116 35, Athens, Greece. Electronic address: achatzi@eie.gr.
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Chatziioannou
authors.affiliation: School of Chemical Engineering, National Technical University of Athens, 9 Iroon Polytechneiou, Zografou, 157 80, Athens, Greece. Electronic address: kolisis@chemeng.ntua.gr.
authors.forename: Fragiskos N
authors.initials: FN
authors.lastname: Kolisis
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens, 15771, Greece. Electronic address: marakos@pharm.uoa.gr.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Marakos
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, Athens, 15771, Greece. Electronic address: pouli@pharm.uoa.gr.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pouli
authors.affiliation: GP Livanos and M Simou Laboratories, 1st Department of Critical Care Medicine & Pulmonary Services, Evangelismos Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, 3 Ploutarchou St., 106 75, Athens, Greece. Electronic address: elloutrar@med.uoa.gr.
authors.forename: Heleni
authors.initials: H
authors.lastname: Loutrari
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D015195:Drug Design; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D059467:Transcriptome / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; C118531:pyrazolopyridine
keywords: Angiogenesis; Gene ontology; Microarray; Pyrazolo[3,4-c]pyridines; Receptor tyrosine kinase inhibitors; Vascular endothelial growth factor