1. Photochemical generation and the reactivity of o-naphthoquinone methides in aqueous solutions
Selvanathan Arumugam, Vladimir V Popik J Am Chem Soc. 2009 Aug 26;131(33):11892-9. doi: 10.1021/ja9031924.
Irradiation of 3-hydroxy-2-naphthalenemethanol (3a) and 2-hydroxy-1-naphthalenemethanol (4a) results in efficient (Phi(254) = 0.17 and 0.20) dehydration and the formation of isomeric naphthoquinone methides, 2,3-naphthoquinone-3-methide (1) and 1,2-naphthoquinone-1-methide (2), respectively. In aqueous solution, naphthoquinone methides 1 and 2 undergo rapid hydration to regenerate starting materials (tau(H2O) (1) = 7.4 ms and tau(H2O) (2) = 4.5 ms at 25 degrees C). The hydration reaction is strongly catalyzed by the hydroxide ion but shows acid catalysis only at pH < 1. Reactive intermediates 1 and 2 can be intercepted by other nucleophiles, such as the azide ion (k(N3)(1) = 2.0 x 10(4) M(-1) s(-1) and k(N3)(2) = 3.0 x 10(4) M(-1) s(-1)) or thiol (k(SH)(1) = 2.2 x 10(5) M(-1) s(-1) and k(SH)(2) = 3.3 x 10(5) M(-1) s(-1)). Ethyl vinyl ether readily reacts with 1 and 2 (k(DA)(1) = 4.1 x 10(4) M(-1) s(-1) and k(DA)(2) = 6.0 x 10(4) M(-1) s(-1)) to produce Diels-Alder adducts in excellent yield. o-Naphthoquinone methides 1 and 2 were also generated by photolysis of 3-ethoxymethyl- (3b) and 1-(ethoxymethyl)-2-naphthols (4b), as well as from (2-hydroxy-3-naphthyl)methyl- (3c) and [(2-hydroxy-1-naphthyl)methyl] trimethylammonium iodides (4c). Laser flash photolysis of 3a,b and 4a,b allows the detection of short-lived (tau(25 degrees C) approximately 12 micros) precursors of naphthoquinone methides 1 and 2. On the basis of the precursor reactivity and the results of DFT calculations, 2H-naphthoxete structure was assigned to these species.
2. Macromolecular adducts of butadiene
Tretyakova NYu, Y P Lin, P B Upton, R Sangaiah, J A Swenberg Toxicology. 1996 Oct 28;113(1-3):70-6. doi: 10.1016/0300-483x(96)03429-4.
Butadiene (BD) is an important industrial chemical classified as a probable human carcinogen. Marked species differences in susceptibility to the carcinogenic effects of BD have been observed, possibly due to the differences in its metabolism. In this work, guanine and adenine adducts formed by the reactive metabolites of BD in vitro were isolated and structurally characterized by UV spectroscopy, liquid secondary ion mass spectrometry and tandem mass spectrometry, electrospray mass spectrometry and nuclear magnetic resonance spectroscopy. The adducts were prepared by reacting purine nucleobases or nucleosides with epoxybutene (EB) or diepoxybutane (DEB) followed by HPLC separation. The reaction of guanine (Gua) with EB resulted in two isomeric products, N7-(2-hydroxy-3-buten-1-yl)guanine (EB-Gua I) and N7-(1-hydroxy-3-buten-2-yl)guanine (EB-Gua II). The reaction of adenine at N3 led to the formation of N3-(2-hydroxy-3-buten-1-yl)adenine (EB-Ade I) and N3-(1-hydroxy-3-buten-2-yl) (EB-Ade II). The major guanine adduct with DEB was identified as N7-(2',3', 4'-trihydroxybutyl)guanine (DEB-Gua-I). Three products formed from the reaction of DEB with adenine at pH 7 were identified as N3, N7 and N9-(2',3',4'-trihydroxybutyl)adenines (DEB-Ade I, II and III, respectively). Our results indicate that nucleophilic nitrogens of guanine and adenine first attack one of the epoxy groups of DEB giving (2'-hydroxy-3',4'-epoxybutane-1-yl) intermediates which can be rapidly hydrolyzed to the corresponding (2',3',4'-trihydroxybutyl) adducts or form cross-links with DNA or proteins. N7 and N3 adducts of Ade and Gua are expected to undergo spontaneous depurination and repair by methylpurine glycosylase and therefore may be useful as biomarkers of exposure in urine. The preliminary data on quantification of EB-induced N-terminal valine hemoglobin adducts in red blood cells of exposed mice and rats using modified Edman degradation followed by GC-NI MS was investigated. The amount of EB-N-terminal valine adducts in mouse globin was about 3 times greater than that in rats which may be explained by higher rates of the formation and/or limited detoxification of EB in mice. Female rats and mice had greater amounts of hemoglobin adducts than males.
