Previous studies have shown that 6-nitrochrysene (6-NC) is a potent mutagen in bacteria and induces mammary carcinoma in rats. It is an exceptionally potent carcinogen in newborn mice. 6-NC is metabolically activated by two pathways, which include only nitroreduction and both nitroreduction and ring oxidation. After metabolic activation via the nitroreduction pathway, 6-NC reacts with DNA to give two regioisomeric adducts of 2'-deoxyguanosine, a C8-modified 2'-deoxyadenosine, N-(dA-8-yl)-6-AC, and a major C8-modified 2'-deoxyinosine adduct, N-(dI-8-yl)-6-AC. The inosine adduct is believed to be the deamination product of the C8-deoxyadenosine adduct. To enable further biochemical studies and to understand the mechanism of deamination, we have synthesized both N-(dA-8-yl)-6-AC and N-(dI-8-yl)-6-AC utilizing palladium-catalyzed Buchwald-Hartwig cross-coupling chemistry. Their conformation preference has been investigated by NMR spectroscopy and DFT calculations. Our preliminary results show <i>syn</i> conformational preference at the glycosidic bond in these adducts. The investigation of the chemical stability of N-(dA-8-yl)-6-AC and N-(dI-8-yl)-6-AC adducted nucleosides under biologically relevant conditions are ongoing using UV/Vis spectroscopy, HPLC, NMR, and mass spectrometry.

Conformational preference and chemical stability of 6-nitrochrysene modified 2'-deoxynucleosides

2019 Spring National Meeting

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