title: Design, synthesis, docking studies and biological evaluation of novel dihydro-1,3,5-triazines as human DHFR inhibitors.
abstract: 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 IC50values 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 IC50values ranging from 0.79 to 0.001 μM. The antitumor activity in vivo of compound 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.
authors.affiliation: Shanghai Key Lab.of Anti-infectives, State Key Lab.of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, China.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Shanghai Key Lab.of Anti-infectives, State Key Lab.of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, China.
authors.forename: Kuaile
authors.initials: K
authors.lastname: Lin
authors.affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, 430030, Hubei, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, Singapore 117543.
authors.forename: Wai-Keung
authors.initials: WK
authors.lastname: Chui
authors.affiliation: Shanghai Key Lab.of Anti-infectives, State Key Lab.of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, China. Electronic address: zhouweicheng58@163.com.
authors.forename: Weicheng
authors.initials: W
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D014227:Triazines; D013762:Tetrahydrofolate Dehydrogenase
keywords: 1,3,5-Triazine; Antitumor activities; Docking study; Triazaspirodiene; hDHFR inhibitors