Utility of 5 %26apos;-O-2,7-Dimethylpixyl for Solid-Phase Synthesis of Oligonucleotides Containing Acid-Sensitive 8-Aryl-Guanine Adducts

作者：Sproviero Michael; Rankin Katherine M; Witham Aaron A; Manderville Richard A^*

来源：Journal of Organic Chemistry, 2014, 79(2): 692-699.

DOI：10.1021/jo4024842

To study the structural and biological impact of 8-aryl-2%26apos;-deoxyguanosine adducts, an efficient protocol is required to incorporate them site-specifically into oligonucleotide substrates. Traditional phosphoramidite chemistry using 5%26apos;-O-DMT protection can be limiting because 8-aryl-dG adducts suffer from greater rates of acid-catalyzed depurination than dG and are sensitive to the acidic deblock conditions required to remove the DMT group. Herein we show that the 5%26apos;-O-2,7-dimethylpixyl (DMPx) protecting group can be used to limit acid exposure and improve DNA synthesis efficiency for DNA substrates containing 8-aryl-dG adducts. Our studies focus on 8-aryl-dG adducts with 8-substituents consisting of furyl ((Fur)dG) phenyl ((Ph)dG), 4-cyanophenyl ((CNPh)dG), and quinolyl ((Q)dG). These adducts differ in ring size and sensitivity to acid-promoted deglycosylation. A kinetic study for adduct hydrolysis in 0.1 M aqueous HCl determined that (Fur)dG was the most acid-sensitive (55.2-fold %26gt; dG), while (Q)dG was the most resistant (5.6-fold %26gt; dG). The most acid-sensitive (Fur)dG was chosen for optimization of solid-phase DNA synthesis. Our studies show that the 5%26apos;-O-DMPx group can provide a 4-fold increase in yield compared to 5%26apos;-O-DMT for incorporation of (Fur)dG into DNA substrates critical for determining adduct impact on DNA synthesis and repair.

• 出版日期2014-1-17