title: Design, synthesis and biological evaluation of 3,9-diazatetraasteranes as novel matrilysin inhibitors.
abstract: Matrilysin is an ideal biological target to develop novel inhibitors because it is overexpressed in malignant tumour cells. A series of 3,9-diazatetraasteranes was designed as inhibitors of matrilysin, which was an ideal biological target because it is responsible for aggressive malignant phenotypes and poor prognoses implicated in many cancers. Docking simulation supported the initial pharmacophore hypothesis and suggested a common interaction mechanism of 3,9-diazatetraasteranes with the catalytic site of matrilysin. The 3,9-diazatetraasteranes were synthesized by the photocyclization of 4-aryl-1,4-dihydropyridines, and their structures were determined using (1) H NMR, (13) C NMR and MS. The inhibitory activities of these compounds on matrilysin were investigated in vitro using an MTT assay in A549 (small cell lung cancer) cells. The results show that the 3,9-diazatetraasteranes can inhibit the growth of A549 tumour cells. The best IC50 value is approximately 50 μm. This result indicates that 3,9-diazatetraasteranes will be useful pharmacological tools for the investigation of matrilysin inhibitors.
authors.affiliation: College of Life Science and Bio-engineering, Beijing University of Technology, Pingleyuan Street No. 100, Chaoyang District, Beijing, 100124, China.
authors.forename: Yanlan
authors.initials: Y
authors.lastname: Liu
authors.forename: Hongbo
authors.initials: H
authors.lastname: Tan
authors.forename: Hong
authors.initials: H
authors.lastname: Yan
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Song
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000737:chemistry* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D013816:Thermodynamics
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D020783:Matrix Metalloproteinase 7
keywords: 3,9-diazatetraasteranes; 4-aryl-1; 4-dihydropyridines; matrilysin inhibitors; photocyclization