Radical and Nitrenoid Reactivity of 3‑Halo-3-phenyldiazirines

3-Halo-3-phenyl-3<i>H</i>-diazirines (halogen = Br or Cl) undergo a dissociative single-electron transfer from alkyllithiums (RLi) in THF-based solvent mixtures. The resulting 3-phenyldiazirinyl radical, observed by EPR spectroscopy, is eventually transformed to benzonitrile. In Et₂O, 2 equiv of RLi add to both nitrogens of halodiazirine NN bond, affording <i>N,N</i>′-dialkylbenzamidines. The nitrenoid reactivity of some <i>N</i>-alkyl-1<i>H</i>-diazirine intermediates is manifested by their insertion into the α-C–H bond of THF or Et₂O

Direct Arylation of Adenine by Fluoro- and Chloronitrobenzenes: Effect of Microwaves

<div><p></p><p>Direct arylation of adenine with fluoro- and chloronitrobenzenes leads to mixtures of <i>N</i>9 and <i>N</i>7 substituted adenines. After separation by column chromatography, the individual isomers can be efficiently hydrogenated on Pd to give the corresponding aminophenyladenines. A significant enhancement of the reaction rate by microwave irradiation was observed. This two-step procedure was found to be a feasible route to otherwise hardly available 7-aminophenyladenines. Correlation between calculated shielding constants and experimental values of chemical shifts in ¹³C and ¹⁵N NMR was used for assignment of the site of substitution.</p> <p>[Supplementary materials are available for this article. Go to the publisher's online edition of <i>Synthetic Communications</i>® for the following free supplemental resource(s): Full experimental and spectral details.]</p> </div

Hydrolytic Cleavage Products of Globin Adducts in Urine as Possible Biomarkers of Cumulative Dose: Proof of Concept Using Styrene Oxide as a Model Adduct-Forming Compound

A new experimental model was designed to study the fate of globin adducts with styrene 7,8-oxide (SO), a metabolic intermediate of styrene and a model electrophilic compound. Rat erythrocytes were incubated with SO at 7 or 22 °C. Levels of specific amino acid adducts in globin were determined by LC/MS analysis of the globin hydrolysate, and erythrocytes with known adduct content were administered intravenously to recipient rats. The course of adduct elimination from the rat blood was measured over the following 50 days. In the erythrocytes incubated at 22 °C, a rapid decline in the adduct levels on the first day post-transfusion followed by a slow phase of elimination was observed. In contrast, the adduct elimination in erythrocytes incubated at 7 °C was nearly linear, copying elimination of intact erythrocytes. In the urine of recipient rats, regioisomeric SO adducts at cysteine, valine, lysine, and histidine in the form of amino acid adducts and/or their acetylated metabolites as well as SO-dipeptide adducts were identified by LC/MS supported by synthesized reference standards. <i>S</i>-(2-Hydroxy-1-phenylethyl)­cysteine and <i>S</i>-(2-hydroxy-2-phenylethyl)­cysteine, the most abundant globin adducts, were excreted predominantly in the form of the corresponding urinary mercapturic acids (HPEMAs). Massive elimination of HPEMAs via urine occurred within the first day from the erythrocytes incubated at both 7 and 22 °C. However, erythrocytes incubated at 7 °C also showed a slow second phase of elimination such that HPEMAs were detected in urine up to 50 days post-transfusion. These results indicate for the first time that globin adducts can be cleaved in vivo to modified amino acids and dipeptides. The cleavage products and/or their predictable metabolites are excreted in urine over the whole life span of erythrocytes. Some of the urinary adducts may represent a new type of noninvasive biomarker for exposure to adduct-forming chemicals