Discovery of novel tricyclic pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine derivatives as VEGFR-2 inhibitors
Abdel Aziz, Yasmine M; Said, Mohamed M; El Shihawy, Hosam A; Abouzid, Khaled;
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.
Other data
Title | Discovery of novel tricyclic pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine derivatives as VEGFR-2 inhibitors | Authors | Abdel Aziz, Yasmine M; Said, Mohamed M; El Shihawy, Hosam A; Abouzid, Khaled | Keywords | Docking studies;Inhibitors;Kinase;Pyridothienopyrimidine;VEGFR-2 | Issue Date | Jun-2015 | Publisher | ACADEMIC PRESS INC ELSEVIER SCIENCE | Journal | Bioorganic Chemistry | Volume | 60 | Start page | 1 | End page | 12 | ISSN | 0045-2068 | DOI | 10.1016/j.bioorg.2015.03.004 | PubMed ID | 25899678 | Scopus ID | 2-s2.0-84928039982 | Web of science ID | WOS:000357664400001 |
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