title: Synthesis, structure analysis, antitumor evaluation and 3D-QSAR studies of 3,6-disubstituted-dihydro-1,2,4,5-tetrazine derivatives.
abstract: 3,6-Diaryl-dihydro-1,2,4,5-tetrazine derivatives were synthesized and their structures were confirmed by single-crystal X-ray diffraction. Monosubstituted dihydrotetrazines are the 1,4-dihydro structure, but disubstituted dihydrotetrazines are the 1,2-dihydro structure. The results of further research indicated there may be a rearrangement during the synthesis process of disubstituted dihydrotetrazines. Their antitumor activities were evaluated against A-549 and P388 cells in vitro. The results showed several compounds to be endowed with cytotoxicity in the low micromolar range. Two compounds were highly effective against A-549 cell and IC50 values were 0.575 and 2.08 μM, respectively. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out on 37 1,2,4,5-tetrazine derivatives with antitumor activity against A-549 cell. Models with good predictive abilities were generated with the cross validated q(2) values for CoMFA and CoMSIA being 0.744 and 0.757, respectively. Conventional r(2) values were 0.978 and 0.988, respectively, the predicted R(2) values were 0.916 and 0.898, respectively. The results provide the tool for guiding the design and synthesis of novel and more potent tetrazine derivatives.
authors.affiliation: College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, People's Republic of China. Electronic address: rgw@zjut.edu.cn.
authors.forename: Guo-Wu
authors.initials: GW
authors.lastname: Rao
authors.forename: Cui
authors.initials: C
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Zhen-Guo
authors.initials: ZG
authors.lastname: Zhao
authors.forename: Wei-Xiao
authors.initials: WX
authors.lastname: Hu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014961:X-Ray Diffraction
chemical_list: D000970:Antineoplastic Agents; D013777:Tetrazoles
keywords: 3D-QSAR; Antitumor activity; CoMFA; CoMSIA; Tetrazine; X-ray diffraction