Manderville, Richard A - University of Guelph

研究领域

Our research in the area of biochemical toxicology focuses on the structural and biological impact of DNA adducts formed by phenolic toxins. Our laboratory has determined that certain phenolic carcinogens attach covalently to DNA and form carbon-(C) and oxygen-(O)-bonded C8-deoxyguanosine (dG) adducts through the intermediacy of the phenoxyl radical. Phenoxyl radicals are one-electron oxidation products of phenols that have been identified in numerous biological systems and are implicated in cancer and aging. The long-term goal of this project is to provide the tools needed to better understand the consequences of C8-dG attachment by phenolic substrates that include: human-made toxins, natural xenobiotics, and anticancer agents. To achieve this goal, synthetic organic chemistry is utilized to convert dG into various C- and O-linked C8-aryl-dG adducts. The modified nucleoside is converted into a phosphoramidite and incorporated into oligonucleotide substrates using solid-phase DNA synthesis to afford adducted DNAs containing a single C- or O-linked adduct. Optical spectroscopies (UV-vis, fluorescence and circular dichroism) are then used to determine the impact of the lesion on duplex DNA. The adducted DNAs are also used as substrates in primer-extension assays with various DNA polymerase enzymes to determine the biological impact of the modified base. Students interested in molecular toxicology, organic and biochemistry, are encouraged to read some of our recent publications and inquire about possible projects in this area of biochemical toxicology.

近期论文

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87. Sproviero, M.; Rankin, K. M.; Witham, A. A.; Manderville, R. A., Utility of 5'-O-2,7-Dimethylpixyl for Solid-Phase Synthesis of Oligonucleotides Containing Acid-Sensitive 8-Aryl-Guanine Adducts. J. Org. Chem. 2014, 79 (2), 692-699. 86. Sproviero, M.; Manderville, R. A., Harnessing G-tetrad scaffolds within G-quadruplex forming aptamers for fluorescence detection strategies. Chem. Commun., 2014, 50, 3097-3099. 85. Sproviero, M.; Fadock, K. L.; Witham, A. A.; Manderville, R. A.; Sharma, P.; Wetmore, S. D., Electronic tuning of fluorescent 8-aryl-guanine probes for monitoring DNA duplex-quadruplex exchange. Chem. Sci. 2014, 5 (2), 788-796. 84. Kuska, M. S.; Witham, A. A.; Sproviero, M.; Manderville, R. A.; Majdi Yazdi, M.; Sharma, P.; Wetmore, S. D., Structural Influence of C8-Phenoxy-Guanine in the NarI Recognition DNA Sequence. Chem. Res. Toxicol. 2013, 26 (9), 1397-1408. 83. Kuska, M.S.; Majdi Yazdi, M.; Witham, A.A.; Dahlmann, H.A.; Sturla, S.J.; Wetmore, S.D.; Manderville, R.A. Influence of Chlorine Substitution on the Hydrolytic Stability of Biaryl Ether Nucleoside Adducts Produced by Phenolic Toxins. J. Org. Chem. 2013, 78, 7176-7185. 82. Sharma, P.; Manderville, R. A.; Wetmore, S. D. Modeling the Conformational Preference of the Carbon-Bonded Covalent Adduct Formed upon Exposure of 2′-Deoxyguanosine to Ochratoxin A. Chem. Res. Toxicol. 2013, 26, 803-816. 81. Rankin, K.M.; Sproviero, M.; Rankin, K.; Sharma, P.; Wetmore, S.D.; Manderville, R.A. C8-Heteroaryl-2′-deoxyguanosine Adducts as Conformational Fluorescent Probes in the NarI Recognition Sequence. J. Org. Chem. Featured Article 2012, 77, 10498-10508. 80. Manderville, R.A.; Omumi, A.; Rankin (née Schlitt), K.M.; Wilson, K.; Millen, A.L.; Wetmore, S.D. A Fluorescent C-Linked C8-Aryl-Guanine Probe for Distinguishing syn from anti Structures in Duplex DNA. Chem. Res. Toxicol. 2012, 25, 1271−1282. 79. Omumi, A.; McLaughlin, C.K.; Ben-Israel, D.; Manderville, R.A. Application of a Fluorescent C-Linked Phenolic Purine Adduct for Selective N7-Metalation of DNA. J. Phys. Chem. B, 2012, 116, 6158-6165. 78. Tozlovanu, M.; Canadas, D.; Pfohl-Leszkowicz, A.; Frenette, C.; Paugh, R. J.; Manderville, R.A. Glutathione Conjugates of Ochratoxin A as Biomarkers of Exposure. Arh. Hig. Rada Toksikol. (Archives of Industrial Hygiene and Toxicology) 2012, 63, 417-427. Special Issue, Articles presented at the Symposium “Power of Fungi and Mycotoxins in Health and Disease” Primošten, Croatia, October 19-22, 2011. 77. Akman, S.A.; Adams, M.; Case, D.; Park, G.; Manderville, R.A. Mutagenicity of Ochratoxin A and Its Hydroquinone Metabolite in the supF Gene of the Mutation Reporter Plasmid pS189. Toxins 2012, 4, 267-280. Special Issue “Ochratoxins 2012”. 76. Witham. A.A.; Beach, D.G.; Gabryelski, W.; Manderville, R.A. Hydroxyl Radical-Induced Oxidation of a Phenolic C-Linked-2′-Deoxyguanosine Adduct Yields a Reactive Catechol. Chem. Res. Toxicol. 2012, 25, 315-325. 75. Pfohl-Leszkowicz, A.; Manderville, R.A. An Update on Direct Genotoxicity as a Molecular Mechanism of Ochratoxin A Carcinogenicity. Chem. Res. Toxicol. 2012, 25, 252-262. 74. Hadjeba-Medjdoub, K.; Tozlovanu, M.; Pfohl-Leszkowicz, A.; Frenette, C.; Paugh, R.J.; Manderville, R.A. Structure-Activity Relationships Imply Different Mechanisms of Action for Ochratoxin A-Mediated Cytotoxicity and Genotoxicity. Chem. Res. Toxicol. 2012, 25, 181-190. 73. Millen, A.L.; Kamenz, B.L.; Leavens, F.M.V.; Manderville, R.A.; Wetmore, S.D. Conformational Flexibility of C8-Phenoxyl-guanine Adducts in Deoxydinucleoside Monophosphates. J. Phys. Chem. B 2011, 115, 12993-13002. 72. Omumi, A.; Millen, A.L.; Wetmore, S.D.; Manderville, R.A. Fluorescent Properties and Conformational Preferences of C-Linked Phenolic-DNA Adducts. Chem. Res. Toxicol. 2011, 24, 1694-1709. 71. Schlitt, K.M.; Millen, A.L.; Wetmore, S.D.; Manderville, R.A. “An Indole-linked C8-Deoxyguanosine Nucleoside acts as a Fluorescent Reporter of Watson-Crick Versus Hoogsteen Base Pairing” Org. Biomol. Chem. 2011, 9, 1565-1571. 70. Omumi, A.; Beach, D.G.; Baker, M.; Gabryelski, W.; Manderville, R.A. “Post-Synthetic Guanine Arylation of DNA by Suzuki-Miyaura Cross-Coupling” J. Am. Chem. Soc. 2011, 133, 42-50. 69. Sagoo, S.; Beach, D.G.; Manderville, R.A.; Gabryelski, W. “Tautomerization in Gas-Phase Ion Chemistry of Isomeric C-8 Deoxyguanosine Adducts from Phenol-Induced DNA Damage” J. Mass. Spectrom. 2011, 46, 41-49. 68. Millen, A.L.; Churchill, C.D.M.; Manderville, R.A.; Wetmore, S.D. “Effect of Watson-Crick and Hoogsteen Base Pairing on the Conformational Stability of C8-Phenoxyl-2′-deoxyguanosine Adducts” J. Phys. Chem. B 2010, 114, 12995-13004. 67. Jennings-Gee, J.E.; Tozlovanu, M.; Manderville, R.A.; Miller, M.S.; Pfohl-Leszkowicz, A.; Schwartz, G.G. "Ochratoxin A: In Utero Exposure in Mice Induces Adducts in Testicular DNA" Toxins 2010, 2, 1428-1444. 66. Millen, A.L.; Manderville, R.A.; Wetmore, S.D. “Conformational Flexibility of C8-Phenoxyl-2′-deoxyguanosine Nucleotide Adducts” J. Phys. Chem. B 2010, 114, 4373-4382. 65. Mantle, P.G.; Faucet-Marquis, V.; Manderville, R.A.; Squillaci, B.; Pfohl-Leszkowicz, A. “Structures of Covalents Adducts Between DNA and Ochratoxin A: A New Factor in Debate About Genotoxicity and Human Risk Assessment” Chem. Res. Toxicol. 2010, 23, 89-98. 64. Manderville, R.A. “DNA Damage by Phenoxyl Radicals” In: Marc Greenberg, editor, Radical and Radical Ion Reactivity in Nucleic Acid Chemistry, John Wiley & Sons, 2009, Chapter 14, pp. 421-443. 63. Schlitt, M.K.; Sun, K.M.; Paugh, R.J.; Millen, A.L.; Navarro-Whyte, L.; Wetmore, S.D.; Manderville, R.A.“Concerning the Hydrolytic Stability of 8-Aryl-2'-deoxyguanosine Nucleoside Adducts: Implications for Abasic Site Formation at Physiological pH” J. Org. Chem. Featured Article 2009, 74, 5793-5802.