DNA methylating agents are abundant in the environment and are sometimes used in cancer chemotherapy. They react with DNA to form methyl-DNA adducts and byproduct lesions that can be both toxic and mutagenic. Foremost among the mutagenic lesions is O 6 -methylguanine (m6G), which base pairs with thymine during replication to cause GC→AT mutations. The gpt delta C57BL/6J mouse strain of Nohmi et al. (Mol. Mutagen, 1996;28:465-70) reliably produces mutational spectra of many DNA damaging agents. In this work, mouse embryo fibroblasts (MEFs) were made from gpt delta C57BL/6J mice and evaluated as a screening tool to determine the qualitative and quantitative features of mutagenesis by N-methyl-N-nitrosourea (MNU), a direct-acting DNA alkylator that serves as a model for environmental N-nitrosamines, such as Nnitrosodimethylamine and therapeutic agents such as temozolomide. The DNA repair protein MGMT (O 6 -methylguanine DNA methyltransferase) protects against environmental mutagenesis by DNA methylating agents and, by removing m6G, limits the therapeutic potential of temozolomide in cancer therapy. The gpt delta MEFs were treated with MNU to establish dosedependent toxicity. In parallel, MNU mutagenicity was determined in the presence and absence of the MGMT inhibitor AA-CW236 (4-(2-(5-(chloromethyl)-4-(4-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)ethyl)-3,5-dimethylisoxazole). With and without the inhibitor, the principal mutagenic event of MNU was GC→AT, but more mutations were observed when the inhibitor was present. Evidence that the mutagenic lesion was m6G was based on mass spectral data collected using O 6 -methyl-d 3 -guanine as an internal standard; m6G levels were higher in AA-CW236 treated MEFs by an amount proportional to the higher mutation
The boron dipyrromethene (BODIPY) triads consisting of two triphenylamine units as electron donor (D) and BODIPY core as electron acceptor (A; B3, and B4) have been synthesized using facile palladium cross‐coupling reactions to broaden the absorption of the BODIPY dyes. All dyes and intermediates were characterized by 1H NMR, 11B NMR, 13C NMR, and 19F NMR spectroscopies, UV–Vis spectroscopy, fluorescence spectroscopy, cyclic voltammetry, and time‐dependent density functional theory calculations. It was found that an increase in conjugation to the BODIPY core systematically extended the absorption and emission wavelength maxima. As a consequence, B4 containing the D–π–A–π–D structure, exhibited the longest absorption and emission maxima at 597 and 700 nm, respectively, with 1.8 eV in optical bandgap. The 96 nm red‐shifted absorption of B4 as compared to the unsubstituted BODIPY (B1) indicated the effective electronic communication between triphenylamine and BODIPY. This suggested that the proper alignment of triphenylamine and BODIPY triad could lead to broader absorption and suitable low energy bandgap. Furthermore, the molecular modeling has been employed to analyze the electronic and optical properties of the dyes. We found that the optical, electrochemical, and theoretical bandgaps of all dyes were in good agreement.
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