Carmelo J. Rizzo, Ph.D.


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Faculty Appointments
Vice Chair of Chemistry Professor of Chemistry Professor of Biochemistry
Ph.D., Chemistry, Organic, University of Pennsylvania, Philadelphia, PennsylvaniaB.S., Temple University, Philadelphia, Pennsylvania
Office Address
VU Station B 351822
7332 Stevenson Center
Research Description
Synthesis of oligonucleotides containing structurally defined carcinogen adducts: The first step of chemical carcinogenesis is the covalent modification of DNA with electrophiles. If these modifications are not repaired, they may compromise the fidelity of DNA replication leading to mutations and possibly cancer. To better understand the structure, mutagenicity and repair of such DNA-carcinogen adducts, we are developing synthetic methods for the preparation of oligonucleotides that have been modified by a carcinogen. The challenge of this work is that the carcinogen adduct must be incorporated site-specifically and in a stereochemically defined manner. We have develop an efficient route for the preparation of C8-deoxyguanosine adducts of mutagenic amines, such as those found in cooked meats. One example is the food mutagen known as IQ, which has been shown to be a potent mutagen in the Ames assay. A second class of DNA adducts we are synthesizing are those from a,b-unsaturated aldehydes which are products of lipid peroxidation. One example of such an endogenous genotoxin is 4-hydroxynonenal (4-HNE) which form exocyclic adducts with deoxyguanosine, deoxyadenosine and deoxycytidine. The reaction of 4-Hydroxynonenal with deoxyguanosine gives four stereoisomeric products. We have developed a strategy for the site-specific and stereospecific syntheses of oligonucleotides containing covalent 4-HNE adducts. This will allow us to examine the role of stereochemistry in the structure and biological activity of these adducts.
Chemical Models for Flavoenzyme Catalysis: Flavoenzymes mediate a wide variety of reaction types making them unique biological catalysts. The organic cofactors responsible for their chemical properties are derivatives of riboflavin (vitamin B2). While a tremendous body of literature now exists on flavin chemistry and biochemistry, the mechanism by which specific interactions between the cofactor and the protein environment modulate the redox and catalytic properties of riboflavin is still not fully understood. We are synthesizing chemical models that mimic specific interactions between the flavin and protein and evaluating how these interactions modulate the redox and catalytic properties of flavin cofactors. The conformation of free flavin is believed to be depended upon the oxidation state of the cofactor. We have synthesized conformationally biased flavin models and showed that the redox chemistry can be driven by conformational consideration. We have also synthesized flavin models with specific hydrogen bonds to the flavin nucleus. A growing number of flavinproteins have been identified in which the cofactors is covalently modified. In the case of some C6-modified flavin cofactors, the covalent modification appears to be an inactivation pathway. We are interested in examining the mechanism by which covalent bonds are form between the C6-position of the cofactor and the substrate during catalysis.
Research Keywords
Organic synthesis, oligonucleotides, cacinogenesis,
Cho YJ, Kozekov ID, Harris TM, Rizzo CJ, Stone MP. Stereochemistry modulates the stability of reduced interstrand cross-links arising from R- and S-alpha-CH3-gamma-OH-1,N2-propano-2'-deoxyguanosine in the 5'-CpG-3' DNA sequence. Biochemistry [print-electronic]. 2007 Mar 3/13/2007; 46(10): 2608-21. PMID: 17305317, PMCID: PMC2581467, DOI: 10.1021/bi061381h, ISSN: 0006-2960.

Elmquist CE, Wang F, Stover JS, Stone MP, Rizzo CJ. Conformational differences of the C8-deoxyguanosine adduct of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) within the NarI recognition sequence. Chem. Res. Toxicol [print-electronic]. 2007 Mar; 20(3): 445-54. PMID: 17311423, PMCID: PMC2743555, DOI: 10.1021/tx060229d, ISSN: 0893-228X.

Stover JS, Ciobanu M, Cliffel DE, Rizzo CJ. Chemical and electrochemical oxidation of C8-arylamine adducts of 2'-deoxyguanosine. J. Am. Chem. Soc [print-electronic]. 2007 Feb 2/21/2007; 129(7): 2074-81. PMID: 17256856, PMCID: PMC2526121, DOI: 10.1021/ja066404u, ISSN: 0002-7863.

Stover JS, Chowdhury G, Zang H, Guengerich FP, Rizzo CJ. Translesion synthesis past the C8- and N2-deoxyguanosine adducts of the dietary mutagen 2-Amino-3-methylimidazo[4,5-f]quinoline in the NarI recognition sequence by prokaryotic DNA polymerases. Chem. Res. Toxicol. 2006 Nov; 19(11): 1506-17. PMID: 17112239, PMCID: PMC3150502, DOI: 10.1021/tx0601455, ISSN: 0893-228X.

Wang H, Kozekov ID, Kozekova A, Tamura PJ, Marnett LJ, Harris TM, Rizzo CJ. Site-specific synthesis of oligonucleotides containing malondialdehyde adducts of deoxyguanosine and deoxyadenosine via a postsynthetic modification strategy. Chem. Res. Toxicol. 2006 Nov; 19(11): 1467-74. PMID: 17112234, PMCID: PMC2441645, DOI: 10.1021/tx060137o, ISSN: 0893-228X.

Choi JY, Stover JS, Angel KC, Chowdhury G, Rizzo CJ, Guengerich FP. Biochemical basis of genotoxicity of heterocyclic arylamine food mutagens: Human DNA polymerase eta selectively produces a two-base deletion in copying the N2-guanyl adduct of 2-amino-3-methylimidazo[4,5-f]quinoline but not the C8 adduct at the NarI G3 site. J. Biol. Chem [print-electronic]. 2006 Sep 9/1/2006; 281(35): 25297-306. PMID: 16835218, PII: M605699200, DOI: 10.1074/jbc.M605699200, ISSN: 0021-9258.

Wang F, DeMuro NE, Elmquist CE, Stover JS, Rizzo CJ, Stone MP. Base-displaced intercalated structure of the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline in the recognition sequence of the NarI restriction enzyme, a hotspot for -2 bp deletions. J. Am. Chem. Soc. 2006 Aug 8/9/2006; 128(31): 10085-95. PMID: 16881637, PMCID: PMC2692337, DOI: 10.1021/ja062004v, ISSN: 0002-7863.

Cho YJ, Wang H, Kozekov ID, Kozekova A, Kurtz AJ, Jacob J, Voehler M, Smith J, Harris TM, Rizzo CJ, Lloyd RS, Stone MP. Orientation of the crotonaldehyde-derived N2-[3-Oxo-1(S)-methyl-propyl]-dG DNA adduct hinders interstrand cross-link formation in the 5'-CpG-3' sequence. Chem. Res. Toxicol. 2006 Aug; 19(8): 1019-29. PMID: 16918240, DOI: 10.1021/tx0600604, ISSN: 0893-228X.

Choi JY, Zang H, Angel KC, Kozekov ID, Goodenough AK, Rizzo CJ, Guengerich FP. Translesion synthesis across 1,N2-ethenoguanine by human DNA polymerases. Chem. Res. Toxicol. 2006 Jun; 19(6): 879-86. PMID: 16780368, PMCID: PMC3130186, DOI: 10.1021/tx060051v, ISSN: 0893-228X.

Otteneder MB, Knutson CG, Daniels JS, Hashim M, Crews BC, Remmel RP, Wang H, Rizzo C, Marnett LJ. In vivo oxidative metabolism of a major peroxidation-derived DNA adduct, M1dG. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2006 Apr 4/25/2006; 103(17): 6665-9. PMID: 16614064, PMCID: PMC1458938, PII: 0602017103, DOI: 10.1073/pnas.0602017103, ISSN: 0027-8424.

Cho YJ, Wang H, Kozekov ID, Kurtz AJ, Jacob J, Voehler M, Smith J, Harris TM, Lloyd RS, Rizzo CJ, Stone MP. Stereospecific formation of interstrand carbinolamine DNA cross-links by crotonaldehyde- and acetaldehyde-derived alpha-CH3-gamma-OH-1,N2-propano-2'-deoxyguanosine adducts in the 5'-CpG-3' sequence. Chem. Res. Toxicol. 2006 Feb; 19(2): 195-208. PMID: 16485895, PMCID: PMC2631444, DOI: 10.1021/tx050239z, ISSN: 0893-228X.

Cho YJ, Kim HY, Huang H, Slutsky A, Minko IG, Wang H, Nechev LV, Kozekov ID, Kozekova A, Tamura P, Jacob J, Voehler M, Harris TM, Lloyd RS, Rizzo CJ, Stone MP. Spectroscopic characterization of interstrand carbinolamine cross-links formed in the 5'-CpG-3' sequence by the acrolein-derived gamma-OH-1,N2-propano-2'-deoxyguanosine DNA adduct. J. Am. Chem. Soc. 2005 Dec 12/21/2005; 127(50): 17686-96. PMID: 16351098, PMCID: PMC2631571, DOI: 10.1021/ja053897e, ISSN: 0002-7863.

Goodenough AK, Kozekov ID, Zang H, Choi JY, Guengerich FP, Harris TM, Rizzo CJ. Site specific synthesis and polymerase bypass of oligonucleotides containing a 6-hydroxy-3,5,6,7-tetrahydro-9H-imidazo[1,2-a]purin-9-one base, an intermediate in the formation of 1,N2-etheno-2'-deoxyguanosine. Chem. Res. Toxicol. 2005 Nov; 18(11): 1701-14. PMID: 16300379, PMCID: PMC3135970, DOI: 10.1021/tx050141k, ISSN: 0893-228X.

Zang H, Goodenough AK, Choi JY, Irimia A, Loukachevitch LV, Kozekov ID, Angel KC, Rizzo CJ, Egli M, Guengerich FP. DNA adduct bypass polymerization by Sulfolobus solfataricus DNA polymerase Dpo4: analysis and crystal structures of multiple base pair substitution and frameshift products with the adduct 1,N2-ethenoguanine. J. Biol. Chem [print-electronic]. 2005 Aug 8/19/2005; 280(33): 29750-64. PMID: 15965231, PII: M504756200, DOI: 10.1074/jbc.M504756200, ISSN: 0021-9258.

Scholdberg TA, Merritt WK, Dean SM, Kowalcyzk A, Harris CM, Harris TM, Rizzo CJ, Lloyd RS, Stone MP. Structure of an oligodeoxynucleotide containing a butadiene oxide-derived N1 beta-hydroxyalkyl deoxyinosine adduct in the human N-ras codon 61 sequence. Biochemistry. 2005 Mar 3/8/2005; 44(9): 3327-37. PMID: 15736943, DOI: 10.1021/bi0482452, ISSN: 0006-2960.

Stover JS, Rizzo CJ. Synthesis of the N2-deoxyguanosine adduct of the potent dietary mutagen IQ. Org. Lett. 2004 Dec 12/23/2004; 6(26): 4985-8. PMID: 15606116, DOI: 10.1021/ol047851m, ISSN: 1523-7060.

Elmquist CE, Stover JS, Wang Z, Rizzo CJ. Site-specific synthesis and properties of oligonucleotides containing C8-deoxyguanosine adducts of the dietary mutagen IQ. J. Am. Chem. Soc. 2004 Sep 9/15/2004; 126(36): 11189-201. PMID: 15355100, DOI: 10.1021/ja0487022, ISSN: 0002-7863.

Brock AK, Kozekov ID, Rizzo CJ, Harris TM. Coupling products of nucleosides with the glyoxal adduct of deoxyguanosine. Chem. Res. Toxicol. 2004 Aug; 17(8): 1047-56. PMID: 15310236, DOI: 10.1021/tx049906z, ISSN: 0893-228X.

West JD, Ji C, Duncan ST, Amarnath V, Schneider C, Rizzo CJ, Brash AR, Marnett LJ. Induction of apoptosis in colorectal carcinoma cells treated with 4-hydroxy-2-nonenal and structurally related aldehydic products of lipid peroxidation. Chem. Res. Toxicol. 2004 Apr; 17(4): 453-62. PMID: 15089087, DOI: 10.1021/tx034248o, ISSN: 0893-228X.

Wang H, Marnett LJ, Harris TM, Rizzo CJ. A novel synthesis of malondialdehyde adducts of deoxyguanosine, deoxyadenosine, and deoxycytidine. Chem. Res. Toxicol. 2004 Feb; 17(2): 144-9. PMID: 14967001, DOI: 10.1021/tx034174g, ISSN: 0893-228X.

Wang H, Kozekov ID, Harris TM, Rizzo CJ. Site-specific synthesis and reactivity of oligonucleotides containing stereochemically defined 1,N2-deoxyguanosine adducts of the lipid peroxidation product trans-4-hydroxynonenal. J. Am. Chem. Soc. 2003 May 5/14/2003; 125(19): 5687-700. PMID: 12733907, DOI: 10.1021/ja0288800, ISSN: 0002-7863.

Kozekov ID, Nechev LV, Moseley MS, Harris CM, Rizzo CJ, Stone MP, Harris TM. DNA interchain cross-links formed by acrolein and crotonaldehyde. J. Am. Chem. Soc. 2003 Jan 1/8/2003; 125(1): 50-61. PMID: 12515506, DOI: 10.1021/ja020778f, ISSN: 0002-7863.

Nechev LV, Kozekov ID, Brock AK, Rizzo CJ, Harris TM. DNA adducts of acrolein: site-specific synthesis of an oligodeoxynucleotide containing 6-hydroxy-5,6,7,8-tetrahydropyrimido[1,2-a]purin-10(3H)-one, an acrolein adduct of guanine. Chem. Res. Toxicol. 2002 May; 15(5): 607-13. PMID: 12018980, PII: tx010181y, ISSN: 0893-228X.

Guo F, Chang BH, Rizzo CJ. An N1-hydrogen bonding model for flavin coenzyme. Bioorg. Med. Chem. Lett. 2002 Jan 1/21/2002; 12(2): 151-4. PMID: 11755342, PII: S0960894X01007120, ISSN: 0960-894X.

Wang H, Rizzo CJ. Stereocontrolled syntheses of all four stereoisomeric 1,N2-deoxyguanosine adducts of the lipid peroxidation product trans-4-hydroxynonenal. Org. Lett. 2001 Nov 11/1/2001; 3(22): 3603-5. PMID: 11678719, PII: ol016810c, ISSN: 1523-7060.

Rizzo CJ. Further computational studies on the conformation of 1,5-dihydrolumiflavin. Antioxid. Redox Signal. 2001 Oct; 3(5): 737-46. PMID: 11761324, DOI: 10.1089/15230860152664948, ISSN: 1523-0864.

Wang F, Wang H, Polavarapu PL, Rizzo CJ. Absolute configuration and conformational stability of (+)-2,5-dimethylthiolane and (-)-2,5-dimethylsulfolane. J. Org. Chem. 2001 May 5/18/2001; 66(10): 3507-12. PMID: 11348137, PII: jo0100401, ISSN: 0022-3263.

Wang Z, Rizzo CJ. Synthesis of the C8-deoxyguanosine adduct of the food mutagen IQ. Org. Lett. 2001 Feb 2/22/2001; 3(4): 565-8. PMID: 11178826, PII: ol006968h, ISSN: 1523-7060.

Wang Z, Prudhomme DR, Buck JR, Park M, Rizzo CJ. Stereocontrolled syntheses of deoxyribonucleosides via photoinduced electron-transfer deoxygenation of benzoyl-protected ribo- and arabinonucleosides. J. Org. Chem. 2000 Sep 9/22/2000; 65(19): 5969-85. PMID: 10987930, PII: jo0003652, ISSN: 0022-3263.

Reibenspies JH, Guo F, Rizzo CJ. X-ray crystal structures of conformationally biased flavin models. Org. Lett. 2000 Apr 4/6/2000; 2(7): 903-6. PMID: 10768182, ISSN: 1523-7060.

Wang Z, Rizzo CJ. Regioselective synthesis of beta-N1- and beta-N3-alloxazine nucleosides. Org. Lett. 2000 Jan 1/27/2000; 2(2): 227-30. PMID: 10814288, PII: ol9913338, ISSN: 1523-7052.

Hasford, JJ, Rizzo, CJ. A Linear Free Energy Substituent Effect on Flavin Redox Chemistry. J. Am. Chem. Soc. 1998; 120((10)): 2251-55.

Prudhomme DR, Wang Z, Rizzo CJ. An Improved Photosensitizer for the Photoinduced Electron-Transfer Deoxygenation of Benzoates and m-(Trifluoromethyl)benzoates. J. Org. Chem. 1997 Nov 11/14/1997; 62(23): 8257-60. PMID: 11671949, ISSN: 1520-6904.

Hasford, JJ, Kemnitzer, W,Rizzo, CJ. Conformational Effects on Flavin Redox Chemistry. J. Org. Chem. 1997; 62((16)): 5244-5.

Park M, Rizzo CJ. Stereocontrolled de Novo Synthesis of beta-2'-Deoxyribonucleosides. J. Org. Chem. 1996 Sep 9/6/1996; 61(18): 6092-3. PMID: 11667437, ISSN: 1520-6904.

Minnie Park and Carmelo J. Rizzo. Stereocontrolled, De Novo Synthesis of beta-2'-Deoxyribonucleosides. J. Org. Chem. 1996; 61: 6092-3.

Available Postdoctoral Position Details
Posted: 3/9/2007
Synthesis of oligonucleotides that are covalently modified by carcinogens for structural and biological studies.