title: Inhibition of tumor cell growth and angiogenesis by 7-aminoalkoxy-4-aryloxy-quinazoline ureas, a novel series of multi-tyrosine kinase inhibitors.
abstract: Several regulatory and signaling molecules governing angiogenesis are targets of interest for the development of drugs in the cancer, including growth factors such as Vascular Endothelial Growth Factor (VEGF) and Platelet-Derived Growth Factor (PDGF). A series of 4-aryloxy-6,7-dimethoxyquinazolines, previously synthesized in our laboratory, has shown a nanomolar inhibition of kinase enzymatic activity of VEGFR, PDGFR and c-Kit. We have therefore studied the impact of the variation in the 7-position substitution of the quinazoline core. Substitution by aminoalkoxy chains led to new highly potent ATP-competitive inhibitors of VEGFR, PDGFR and c-Kit enzyme with IC50 values in the nanomolar range and this substitution has increased greatly antiproliferative activity on cancer cell lines (PC3, MCF7, HT29) and HUVEC (human umbilical vein endothelial cells). One of the most promising compounds (36) was assessed for its ability to limit the induction of web like network of capillary tubes by the human umbilical vascular endothelial cells (HUVEC) and for its ability to inhibit invasion.
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France; Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), UDSL, EA4481, F-59006 Lille, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Ravez
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France; Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), UDSL, EA4481, F-59006 Lille, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Barczyk
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France; Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), UDSL, EA4481, F-59006 Lille, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Six
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France; Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), UDSL, EA4481, F-59006 Lille, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cagnon
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France; Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), UDSL, EA4481, F-59006 Lille, France.
authors.forename: Antonio
authors.initials: A
authors.lastname: Garofalo
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France; Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), UDSL, EA4481, F-59006 Lille, France. Electronic address: laurence.goossens@univ-lille2.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Goossens
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France; Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), UDSL, EA4481, F-59006 Lille, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Depreux
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019073:HT29 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014508:Urea; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Anti-angiogenic agents; Cancer; Multi-kinase inhibitors; PDGFR-ß; VEGFR; c-Kit