SummaryTuberculosis (TB) treatment can cause serious sequelae including adverse effects such as anti-TB drug-induced hepatotoxicity (ATDH). We performed a candidate gene-based association study between single nucleotide polymorphisms (SNPs) in 10 genes in the antioxidant pathway and ATDH susceptibility. The subjects comprised 100 Japanese patients with pulmonary TB who received a treatment regimen including isoniazid and rifampicin. Out of them, 18 patients had ATDH. Thirty-four tag SNPs in 10 genes were analyzed by PCR-restriction fragment length polymorphism or PCR-direct DNA sequencing. The frequencies of alleles and genotypes between patients with and without ATDH were compared in three different genetic models. Statistical analyses revealed that a C/C genotype at rs11080344 in NOS2A, a C/C genotype at rs2070401 in
The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2 4 and NAT2 6A, are useful new biomarkers for predicting anti-TB drug-induced hepatotoxicity.
3-(2H)-isoxazolone is an important skeletal structure in medicinal and agricultural chemistry. However, its synthetic methodology has limited substrate scope and requires unconventional substrate synthesis. Meanwhile, gold-catalyzed intramolecular oxidative cross-coupling involving the 5/6-endo-dig cyclization of substrates bearing an ynone structure has not been reported because of an undesirable protonation as a side-reaction. Thus, we hypothesized that the reactivity of cyclic N-alkoxypropiolamides would suppress protonation and allow dual functionalization. As a result, sequential gold-catalyzed 5-endo-dig cyclization, oxidative cross-coupling, and hydroxylation of N-alkoxypropiolamides was developed to synthesize 4-aryl-3-(2H)-isoxazolones with a hydroxy group. In an optimization study, dimethylformamide (DMF) and H 2 O were effective solvents for the sequential reaction. This method enabled 3-(2H)-isoxazolone backbone synthesis with the introduction of an aryl and hydroxy group in a single procedure. Moreover, a tolerance toward reactive functional groups, such as ketocarbonyl groups, was observed. Some chemical transformations of the synthesized 4-aryl-3-(2H)-isoxazolone were conducted to demonstrate the feasibility of functional group interconversion, CÀ C bond formation, and additional heterocycle synthesis. Notably, a fluorescent tetracyclic heterocycle was obtained by intramolecular oxidative cross-coupling. Control experiments indicated that the reactivity for protonation was suppressed by an alkoxyamide moiety. Therefore, the chemoselectivity of oxyarylation was improved. Finally, density functional theory (DFT) calculations were performed to estimate the reaction pathway, which suggested that ring-opening involving solvents (H 2 O or DMF) is important for these sequential reactions.
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