Discovery of Potent VEGFR-2 Inhibitors based on Furopyrimidine and Thienopyrimidne Scaffolds as Cancer Targeting Agents
Aziz, Marwa A; Serya, Rabah A T; Lasheen, Deena S.; Abdel-Aziz, Amal Kamal; Mansour, Ahmed M; Ahmed Esmat; Singab A.; Khaled A M Abouzid;
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.
Other data
Title | Discovery of Potent VEGFR-2 Inhibitors based on Furopyrimidine and Thienopyrimidne Scaffolds as Cancer Targeting Agents | Authors | Aziz, Marwa A; Serya, Rabah A T; Lasheen, Deena S. ; Abdel-Aziz, Amal Kamal ; Mansour, Ahmed M; Ahmed Esmat ; Singab A. ; Khaled A M Abouzid | Keywords | VEIN ENDOTHELIAL-CELLS;KINASE INHIBITORS;DESIGN;DERIVATIVES;CHEMOTHERAPY;BEVACIZUMAB;CANDIDATES;SORAFENIB;RECEPTORS;SUNITINIB | Issue Date | 15-Apr-2016 | Publisher | NATURE PUBLISHING GROUP | Journal | Scientific Reports | ISSN | 2045-2322 | DOI | 10.1038/srep24460 | PubMed ID | 27080011 | Scopus ID | 2-s2.0-84964255488 | Web of science ID | WOS:000374213600001 |
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