title: Design, synthesis and biological evaluation of new pyrazolyl-ureas and imidazopyrazolecarboxamides able to interfere with MAPK and PI3K upstream signaling involved in the angiogenesis.
abstract: Taking into account the structure activity relationship information given by our previous studies, we designed and synthesized a small library of pyrazolylureas and imidazopyrazolecarboxamides fluorinated on urea moiety and differently decorated on pyrazole nucleus. All compounds were preliminary screened by Western blotting technique to evaluate their activity on MAPK and PI3K pathways by monitoring ERK1/2, p38MAPK and Akt phosphorylation, and also screened with a wound healing assay to assess their capacity in inhibiting endothelial cell migration, using human umbilical vein endothelial cells stimulated with VEGF. Pyrazoles and imidazopyrazoles did not show the same activity profile. SAR consideration showed that specific substituents and their position in pyrazole nucleus, as well as the type of substituent on the phenylurea moiety play a pivotal role in determining increase or decrease of kinases phosphorylation. On the other hand the loss of flexibility in imidazopyrazole derivatives is responsible for activity potentiation. Screening of the compound library for inhibition of endothelial cell migration, a function required for angiogenesis, showed significant activity for compound 3. This compound might interfere with cell migration by modulating the activity of different upstream target kinases. Therefore, compound 3 represents a potential inhibitor of angiogenesis. Furthermore, it may be used as a tool to identify unknown mediators of endothelial migration and thereby unveiling new therapeutic targets for controlling pathological angiogenesis in diseases such as cancers.
authors.affiliation: Department of Pharmacy, Medicinal Chemistry Section, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors.forename: Elda
authors.initials: E
authors.lastname: Meta
authors.affiliation: Department of Pharmacy, Medicinal Chemistry Section, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy. Electronic address: chiara.brullo@unige.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Brullo
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Rue Michel-Servet 1, CH - 1211, Geneva, Switzerland.
authors.forename: Adama
authors.initials: A
authors.lastname: Sidibe
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Rue Michel-Servet 1, CH - 1211, Geneva, Switzerland.
authors.forename: Beat A
authors.initials: BA
authors.lastname: Imhof
authors.affiliation: Department of Pharmacy, Medicinal Chemistry Section, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D042461:Vascular Endothelial Growth Factor A; D014508:Urea; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases
keywords: Akt phosphorylation; ERK1/2 phosphorylation; Imidazopyrazole derivatives; Migration; Pyrazolylureas; p38MAPK phosphorylation