title: Discovery of novel tricyclic pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine derivatives as VEGFR-2 inhibitors.
abstract: In an effort to develop ATP-competitive VEGFR-2 selective inhibitors, a novel series of tricyclic pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine derivatives were designed and synthesized. These compounds were characterized by IR, (1)H NMR, (13)C NMR, elemental and mass spectral analyses. Docking studies have given a partial insight into the molecular determinants of the activity of this novel series in VEGFR-2 kinase active site. Moreover, these compounds were assessed at 10μM for their selective inhibitory activities over a panel of 6 human kinases, namely VEGFR-1/Flt-1, VEGFR-2/KDR, EGFR, CDK5/p25, GSK3α and GSK3β. Compound N-(4,6-dimethylthieno[2,3-b]pyridine)-7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine (9d) exhibited the most potent and selective inhibitory activity against VEGFR-2/KDR over the six human kinases, with an IC50 value 2.6μM. The identification of this hit candidate could aid the design of new tricyclic-based VEGFR-2 kinase modulators.
authors.affiliation: Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt. Electronic address: mohamad_yasmine@yahoo.com.
authors.forename: Yasmine M
authors.initials: YM
authors.lastname: Abdel Aziz
authors.affiliation: Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Said
authors.affiliation: Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
authors.forename: Hosam A
authors.initials: HA
authors.lastname: El Shihawy
authors.affiliation: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
authors.forename: Khaled A M
authors.initials: KA
authors.lastname: Abouzid
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000586:Amination; D006801:Humans; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000601850:thieno(2,3-d)pyrimidine; D000255:Adenosine Triphosphate; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Docking studies; Inhibitors; Kinase; Pyridothienopyrimidine; VEGFR-2