期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 125, 期 -, 页码 1279-1288出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.11.010
关键词
1,3,5-Triazine; Triazaspirodiene; hDHFR inhibitors; Docking study; Antitumor activities
资金
- Natural Science Foundation of Shanghai [15ZR1440200]
A novel series of dihydro-1,3,5-triazine derivatives bearing a heteroatom spiro-ring were designed and synthesized on the basis of molecular flexible docking work, and their biological activities were evaluated. Compounds A2, A5, B1 and B3 showed potent human dihydrofolate reductase (hDHFR) inhibitory activity with IC50 values of 7.46 nM, 3.72 nM, 6.46 nM, 4.08 nM, versus reference drug methotrexate (MTX). From the molecular docking result we concluded that the conformation space generated by deformation of the flexible residue Phe31 is favorable for the binding of the spiro-ring, and inserting heteroatom into spiro ring might increase the binding affinity. There were 24 compounds with broadspectrum antiproliferative activity against several tumor cell lines (HCT116, A549, HL-60, HepG2 and MDA-MB-231) with IC50 values ranging from 0.79 to 0.001 mu M. The antitumor activity in vivo of corn pound A2 was determined in a human alveolar basal epithelial cell line A549 xenograft model. This study offered novel anticancer agents with high inhibitory activity that target hDHFR and have a binding mode of the novel molecular scaffold with hDHFR. This provides potent support for further development of novel hDHFR inhibitors. (C) 2016 Elsevier Masson SAS. All rights reserved.
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