Aryl hydrazines and related compounds have been shown to be carcinogenic but the mechanism is still unclear. C8-Arylguanine adducts, formed from oxidative metabolites of aryl hydrazines, are suspected to be the cause of carcinogenesis. Z-DNA formation facilitated by the aryl adduct are among the potential mechanisms and has been investigated in this study. Z-DNA may be involved in carcinogenesis as several studies have indicated that Z-DNA may play an important role in gene expression and to induce mutagenic genetic deletions. C8-Arylguanine adducts may cause carcinogenesis by promoting the formation of Z-DNA which in turn disturbing gene regulation and leading to mutagenesis. To investigate this hypothesis, we have set out to (1) study the effect of aryl adducts formed from carcinogenic aryl hydrazines on B/Z-DNA equilibrium and (2) seek the relevancy between Z-DNA formation and aryl hydrazine carcinogenesis.
Here, alternating CG decamers containing C8-arylguanine modifications (d(CGCGCG*CGCG)2, G* = C8-tolyl, C8-carboxyphenyl, C8-methoxymethylphenyl, or C8-hydroxymethylphenyl guanine), were prepared through Suzuki coupling and phosphoramidite chemistry. The effect of the aryl adducts on the B/Z-DNA equilibrium were determined by CD and NMR analysis. The experimental results supported by computational study have suggested that all of the aryl modifications examined facilitate B-Z transition by destabilizing the B conformation and/or stabilizing the Z conformation relative to the corresponding unmodified oligonucleotide. Among the aryl adducts, C8-carboxyphenyl adduct has been shown to be best at facilitating B-Z transition followed by C8-phenyl, C8-methoxymethylphenyl, C8-hydroxymethylphenyl, and C8-tolyl respectively. The effect of aryl adducts on B-Z transition is generally correlated with the reported V79 mutagenicity of the aryl hydrazines precursors. This preliminary study has suggested that Z-DNA may be involved or plays a role in aryl hydrazine carcinogenesis.
|Advisor:||Gannett, Peter M.|
|School:||West Virginia University|
|School Location:||United States -- West Virginia|
|Source:||DAI-B 70/10, Dissertation Abstracts International|
|Subjects:||Analytical chemistry, Organic chemistry, Pharmacy sciences|
|Keywords:||Aryl hydrazine, Arylguanine adducts, Carcinogenesis, Z-DNA|
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