New fluorinated diarylureas linked to pyrrolo[2,3-d]pyrimidine scaffold as VEGFR-2 inhibitors: Molecular docking and biological evaluation
Adel, Mai; Abouzid, Khaled;
Abstract
A series of pyrrolo[2,3-d]pyrimidine linked to diarylureas were previously discovered by our group as sorafenib fused congeners, which were endowed with more potent activity as inhibitors to vascular endothelial growth factor receptor (VEGFR2) than sorafenib. Based on these results and on the observation that the fluorinated regorafenib displayed higher VEGFR2 inhibitory activity relative to sorafenib. Therefore, in this study, we sought to develop more potent pyrrolopyrimidine surrogates through introduction of fluorine atom at the phenyl moiety near to the urea moiety mimicking regorafenib. We hypothesized that this would improve the compounds potency. Surprisingly, Compound9epossessed better VEGFR2 inhibitory activity (IC50 = 52.4 nM) compared to standard drug sorafenib, whereas compounds (9b,d and f) showed moderate inhibitory activity. The newly synthesized compounds were tested on 60 human cancer cell lines. Field alignment and a molecular docking study of these compounds into the inactive conformation of VEGFR2 was performed, and theoretical ADME properties were determined.
Other data
Title | New fluorinated diarylureas linked to pyrrolo[2,3-d]pyrimidine scaffold as VEGFR-2 inhibitors: Molecular docking and biological evaluation | Authors | Adel, Mai; Abouzid, Khaled | Keywords | ENDOTHELIAL GROWTH-FACTOR; MULTIKINASE INHIBITOR; KINASE INHIBITORS; ORGANIC FLUORINE; BINDING MODE; DESIGN; DISCOVERY; ANGIOGENESIS; SORAFENIB; RECEPTORS | Issue Date | Oct-2022 | Publisher | ACADEMIC PRESS INC ELSEVIER SCIENCE | Journal | Bioorganic chemistry | Volume | 127 | ISSN | 0045-2068 | DOI | 10.1016/j.bioorg.2022.106006 | PubMed ID | 35820328 | Scopus ID | 2-s2.0-85133873141 | Web of science ID | WOS:000829233200002 |
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