Novel potent substituted 4-amino-2-thiopyrimidines as dual VEGFR-2 and BRAF kinase inhibitors

被引:54
作者
Abdel-Mohsen, Heba T. [1 ]
Omar, Mohamed A. [1 ]
El Kerdawy, Ahmed M. [2 ,3 ,4 ]
Mahmoud, Abeer E. E. [5 ]
Ali, Mamdouh M. [5 ]
El Diwani, Hoda I. [1 ]
机构
[1] Natl Res Ctr, Dept Chem Nat & Microbial Prod, Div Pharmaceut & Drug Ind Res, Cairo, Egypt
[2] Cairo Univ, Fac Pharm, Dept Pharmaceut Chem, Kasr El Aini St,POB 11562, Cairo, Egypt
[3] Cairo Univ, Fac Pharm, Mol Modeling Unit, Kasr El Aini St,POB 11562, Cairo, Egypt
[4] New Giza Univ, Fac Pharm, Dept Pharmaceut Chem, Km 22 Cairo Alexandria Desert Rd, Cairo, Egypt
[5] Natl Res Ctr, Div Genet Engn & Biotechnol, Dept Biochem, Cairo, Egypt
关键词
VEGFR-2; BRAF; Antiproliferative activity; Thiopyrimidines; Synthesis; Molecular docking; ENDOTHELIAL GROWTH-FACTOR; SIGNALING PATHWAY; TYROSINE KINASES; MEK INHIBITION; DESIGN; MUTATIONS; MELANOMA; RAF; HYBRIDIZATION; EXPRESSION;
D O I
10.1016/j.ejmech.2019.06.063
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
In the present study, we report the discovery of a novel class of substituted 4-amino-2-thiopyrimidines as antiangiogenic and antiproliferative agents. Structural hybridization between 4-substituted amino-pyrimidines (VEGFR-2 inhibitors) and 2-thioxopyrimidines (BRAE inhibitors) was carried out to afford substituted 4-amino-2-thiopyrimidines as type II dual VEGFR-2/BRAF inhibitors. Our design strategy was tailored such that the 4-amino-2-thiopyrimidine scaffold is to be accommodated in the central gate area of the inactive DFG-out conformation of both enzymes. On one side, the hydrophobic substituent on the 4-amino group would occupy the hydrophobic back pocket and on the other side the substituent on the sulfide moiety should extend to fit in the hinge region (front pocket). Molecular docking simulations confirmed the ability of the designed compounds to accomplish the key interactions in VEGFR-2 and BRAF active sites. Most of the synthesized substituted 4-amino-2-thiopyrimidines demonstrated potent VEGFR-2 inhibitory activity at submicromolar concentrations. Compounds 8a, 8d, 9c and 9e showed IC50 = 0.17, 0.12, 0.17 and 0.19 mu M, respectively against VEGFR-2 in comparison to sorafenib (I) IC50 = 0.10 mu M and regorafenib (H) IC50 = 0.005 mu M. While compounds 9c, 9d and 10a showed IC50 = 0.15, 0.22 and 0.11 mu M, respectively against BRAF-WT. At 10 mu M concentration 9c revealed promising in vitro broad-spectrum antiproliferative activity against cancer cell lines with growth inhibition percent ranging from 10 to 90%. Moreover, compounds 7b, 8d, 9a, 9b, 9c and 9d showed potent activity against MCF7 cell line (IC50 = 17.18, 17.20, 19.98, 19.61, 13.02 and 16.54 mu M, respectively). On the other hand, compounds 9c, 9d and 10d were found to be the most potent compounds against T-47D cell line (IC50 = 2.18, 8.09 and 4.36 mu M, respectively). Studying the effect of the most potent compounds on VEGFR-2 level in MCF7 cell line revealed that 9c and 9d showed inhibition percent of 84 and 80%, respectively, in comparison to sorafenib (I) (% inhibition = 90%). (C) 2019 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:707 / 722
页数:16
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