title: Discovery of Potent VEGFR-2 Inhibitors based on Furopyrimidine and Thienopyrimidne Scaffolds as Cancer Targeting Agents.
abstract: Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In this study, a series of novel furo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine based-derivatives were designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The synthesized compounds were evaluated for their ability to in vitro inhibit VEGFR-2 kinase enzyme. Seven compounds (15b, 16c, 16e, 21a, 21b, 21c and 21e) demonstrated highly potent dose-related VEGFR-2 inhibition with IC50 values in nanomolar range, of which the thieno[2,3-d]pyrimidine based-derivatives (21b, 21c and 21e) exhibited IC50 values of 33.4, 47.0 and 21 nM respectively. Moreover, furo[2,3-d]pyrimidine-based derivative (15b) showed the strongest inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 99.5% inhibition at 10 μM concentration. Consistent with our in vitro findings, compounds (21b and 21e) orally administered at 5 and 10 mg/kg/day for 8 consecutive days demonstrated potent anticancer activity in Erhlich ascites carcinoma (EAC) solid tumor murine model. Such compounds blunted angiogenesis in EAC as evidenced by reduced percent microvessel via decreasing VEGFR-2 phosphorylation with subsequent induction of apoptotic machinery. Furthermore, Miles vascular permeability assay confirmed their antiangiogenic effects in vivo. Intriguingly, such compounds showed no obvious toxicity.
authors.affiliation: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
authors.forename: Marwa A
authors.initials: MA
authors.lastname: Aziz
authors.affiliation: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
authors.forename: Rabah A T
authors.initials: RA
authors.lastname: Serya
authors.affiliation: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.|Center for Drug Discovery and Development Research, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
authors.forename: Deena S
authors.initials: DS
authors.lastname: Lasheen
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
authors.forename: Amal Kamal
authors.initials: AK
authors.lastname: Abdel-Aziz
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.|Center for Drug Discovery and Development Research, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Esmat
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Mansour
authors.affiliation: Pharmacognosy Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.|Center for Drug Discovery and Development Research, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
authors.forename: Abdel Nasser B
authors.initials: AN
authors.lastname: Singab
authors.affiliation: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.|Center for Drug Discovery and Development Research, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
authors.forename: Khaled A M
authors.initials: KA
authors.lastname: Abouzid
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D055808:Drug Discovery; D005663:Furans / Q000737:chemistry; D006801:Humans; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy; D009952:Ornithine / Q000031:analogs & derivatives* / Q000737:chemistry; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D005663:Furans; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C497346:furornithine; C476003:thienopyrimidine; D009952:Ornithine; D040301:Vascular Endothelial Growth Factor Receptor-2