M Paul Chiarelli

University of Rhode Island, Kingston, RI, United States

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Publications (39)131.08 Total impact

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    ABSTRACT: A surface adlayer is generated on organic single crystals (tetracene and rubrene) using the site specific Diels-Alder reaction and a series of vapor phase dienophiles. X-ray photoelectron spectroscopy (XPS) confirms adsorption on the surfaces of tetracene and rubrene and mass spectrometry demonstrates the reaction's applicability to a range of dienophiles.
    Chemical Communications 04/2013; · 6.38 Impact Factor
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    ABSTRACT: Nucleotide excision repair (NER) is a major repair pathway that recognizes and corrects various lesions in cellular DNA. We hypothesize that damage recognition is an initial step in NER that senses conformational anomalies in the DNA caused by lesions. We prepared three DNA duplexes containing the carcinogen adduct N-(2'-deoxyguanosin-8-yl)-7-fluoro-2-acetylaminofluorene (FAAF) at G(1), G(2) or G(3) of NarI sequence (5'-CCG(1)G(2)CG(3)CC-3'). Our (19)F-NMR/ICD results showed that FAAF at G(1) and G(3) prefer syn S- and W-conformers, whereas anti B-conformer was predominant for G(2). We found that the repair of FAAF occurs in a conformation-specific manner, i.e. the highly S/W-conformeric G(3) and -G(1) duplexes incised more efficiently than the B-type G(2) duplex (G(3)∼G(1)> G(2)). The melting and thermodynamic data indicate that the S- and W-conformers produce greater DNA distortion and thermodynamic destabilization. The N-deacetylated N-(2'-deoxyguanosin-8-yl)-7-fluoro-2-aminofluorene (FAF) adducts in the same NarI sequence are repaired 2- to 3-fold less than FAAF: however, the incision efficiency was in order of G(2)∼G(1)> G(3), a reverse trend of the FAAF case. We have envisioned the so-called N-acetyl factor as it could raise conformational barriers of FAAF versus FAF. The present results provide valuable conformational insight into the sequence-dependent UvrABC incisions of the bulky aminofluorene DNA adducts.
    Nucleic Acids Research 01/2012; 40(9):3939-51. · 8.81 Impact Factor
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    Illicit Drugs in the Environment: Occurrence, Analysis, and Fate Using Mass Spectrometry, 01/2011: pages 321 - 331; , ISBN: 9781118000816
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    ABSTRACT: We report synthesis and characterization of a complete set of alpha,beta-methylene-2'-dNTPs (alpha,beta-m-dNTP; N = A, C, T, G, 12-15) in which the alpha,beta-oxygen linkage of natural dNTP was replaced by a methylene group. These nucleotides were designed to be noncleavable substrates for DNA polymerases. Synthesis entails preparation of 2'-deoxynucleoside 5'-diphosphate precursors, followed by an enzymatic gamma-phosphorylation. All four synthesized alpha,beta-m-dNTPs were found to be potent inhibitors of polymerase beta, with K i values ranging 1-5 microM. During preparation of the dG and dT derivatives of alpha,beta-methylene diphosphate, we also isolated significant amounts of 3,5'-cyclo-dG (16) and 2,5'-cyclo-dT (17), respectively. These novel 2'-deoxycyclonucleosides were formed via a base-catalyzed intramolecular cyclization (N3 --> C5' and O2 --> C5', respectively). In acidic solution, both 16 and 17 underwent glycolysis, followed by complete depurination. When exposed to alkaline conditions, 16 underwent an oxidative deamination to produce 3,5'- cyclo-2'-deoxyxanthosine (19), whereas 17 was hydrolyzed exclusively to dT.
    Journal of Medicinal Chemistry 09/2008; 51(20):6460-70. · 5.61 Impact Factor
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    Lan Gao, Li Zhang, Bongsup P Cho, M Paul Chiarelli
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    ABSTRACT: An analytical method for the structure differentiation of arylamine modified oligonucleotides (ODNs) using on-line LC/MS analysis of raw exonuclease digests is described. Six different dodeca ODNs derived from the reaction of N-acetoxy-N-(trifluoroacetyl)-2-aminofluorene with the dodeca oligonucleotide 5'-CTCGGCGCCATC-3' are isolated and sequenced with this LC/MS method using 3'- and 5'-exonucleases. When the three products modified by a single aminofluorene (AF) are subjected to 3'-exonuclease digestion, the exonuclease will cleave a modified nucleotide but when di-AF modified ODNs are analyzed the 3'-exonuclease ceases to cleave nucleotides when the first modification is exposed at the 3'-terminus. Small abundances of ODN fragments formed by the cleavage of an AF-modified nucleotide were observed when two of the three di-AF modified ODNs were subjected to 5'-exonuclease digestion. The results of the 5'-exonuclease studies of the three di-AF modified ODNs suggest that as the number of unmodified bases between two modifications in an ODN sequence increases, the easier it becomes to sequence beyond the modification closest to the 5'-terminus. The results of this study indicate that the LC/MS method described here would be useful in sequencing ODNs modified by multiple arylamines to be used as templates for site-specific mutagenesis studies.
    Journal of the American Society for Mass Spectrometry 08/2008; 19(8):1147-55. · 3.59 Impact Factor
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    ABSTRACT: Fluorescence spectroscopy was used to study carcinogen-induced conformational heterogeneity in DNA duplexes. The fluorophore 2-aminopurine (AP) was incorporated adjacent (5') to the lesion (G*) in eight different DNA duplexes [d(5'-CTTCT PG* NCCTC-3'):d(5'-GAGGN XTAGAAG-3'), G* = FAF adduct, P = AP, N = G, A, C, T, and X = C, A] modified by FAF [ N-(2'-deoxyguanosin-8-yl)-7-fluoro-2-aminofluorene], a fluorine-tagged model DNA adduct derived from the potent carcinogen 2-aminofluorene. Steady-state measurements showed that fluorescence intensity and Stern-Volmer constants ( Ksv) derived from acrylamide quenching experiments decreased for all carcinogen-modified duplexes relative to the controls, which suggests greater AP stacking in the duplex upon adduct formation. Conformation-specific stacking of AP with the neighboring adduct was evidenced by a sequence-dependent variation in fluorescence intensity, position of emission maximum, degree of emission quenching by acrylamide, and temperature-dependent spectral changes. The magnitude of stacking was in the order of FAF residue in base-displaced stacked (S) > minor groove wedged (W) > major groove B type (B). This work represents a novel utility of AP in probing adduct-induced conformational heterogeneities in DNA duplexes.
    Chemical Research in Toxicology 02/2008; 21(2):445-52. · 3.67 Impact Factor
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    ABSTRACT: The oxidation of cyclohexadiene in a mixed aqueous solvent in the present of azide ion produced 4-azido-2-cyclohexene-1-one, 1, and 2-azido-3-cyclohexene-1-one, 2, in a four electron transfer in about a 70% yield. The overall reaction is a net air oxidation. These enantioselectivies are higher than any obtained previously for addition to 1,3-dienes. The conversion of 1 to 2 involves a [3,3]sigmatropic rearrangement.
    Catalysis Communications - CATAL COMMUN. 01/2008; 9(7):1661-1665.
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    ABSTRACT: A systematic spectroscopic and computational study was conducted in order to probe the influence of base sequences on stacked (S) versus B-type (B) conformational heterogeneity induced by the major dG adduct derived from the model carcinogen 7-fluoro-2-aminofluorene (FAF). We prepared and characterized eight 12-mer DNA duplexes (-AG*N- series, d[CTTCTAG*NCCTC]; -CG*N- series, d[CTTCTCG*NCCTC]), in which the central guanines (G*) were site-specifically modified with FAF with varying flanking bases (N = G, A, C, T). S/B heterogeneity was examined by CD, UV, and dynamic 19F NMR spectroscopy. All the modified duplexes studied followed a typical dynamic exchange between the S and B conformers in a sequence dependent manner. Specifically, purine bases at the 3'-flanking site promoted the S conformation (G > A > C > T). Simulation analysis showed that the S/B energy barriers were in the 14-16 kcal/mol range. The correlation times (tau = 1/kappa) were found to be in the millisecond range at 20 degrees C. The van der Waals energy force field calculations indicated the importance of the stacking interaction between the carcinogen and neighboring base pairs. Quantum mechanics calculations showed the existence of correlations between the total interaction energies (including electrostatic and solvation effects) and the S/B population ratios. The S/B equilibrium seems to modulate the efficiency of Escherichia coli UvrABC-based nucleotide excision repair in a conformation-specific manner: i.e., greater repair susceptibility for the S over B conformation and for the -AG*N- over the -CG*N- series. The results indicate a novel structure-function relationship, which provides insights into how bulky DNA adducts are accommodated by UvrABC proteins.
    Biochemistry 10/2007; 46(40):11263-78. · 3.38 Impact Factor
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    ABSTRACT: The fragment ion formation characteristics of the radical anions generated from hexahydro-1,3,5-trinitrotriazine (RDX) and its three nitroso metabolites were studied using GC/MS with negative chemical ionization (NCI) to understand the fragmentation mechanisms responsible for the formation of the most abundant ions observed in their NCI mass spectra. Ab initio and density functional theory calculations were used to calculate relative free energies for different fragment ion structures suggested by the m/z values of the most abundant ions observed in the NCI mass spectra. The NCI mass spectra of the four nitramines are dominated by ions formed by the cleavage of nitrogen-nitrogen and carbon-nitrogen bonds in the atrazine ring. The most abundant anions in the NCI mass spectra of these nitramines have the general formulas C(2)H(4)N(3)O (m/z 86) and C(2)H(4)N(3)O(2) (m/z 102). The analyses of isotope-labeled standards indicate that these two ions are formed by neutral losses that include two exocylic nitrogens and one atrazine ring nitrogen. Our calculations and observations of the nitramine mass spectra suggest that the m/z 86 and m/z 102 ions are formed from either the (M--NO)(-) or (M--NO(2))(-) fragment anions by a single fragmentation reaction producing neutral losses of CH(2)N(2)O or CH(2)N(2)O(2) rather than a set of sequential reactions involving neutral losses of HNO(2) or HNO and HCN.
    Journal of the American Society for Mass Spectrometry 06/2007; 18(5):835-41. · 3.59 Impact Factor
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    ABSTRACT: The metabolism of the antibacterial fluoroquinolone drug flumequine by Cunninghamella elegans was investigated using cultures grown in Sabouraud dextrose broth with 308microM flumequine. The cultures were extracted with ethyl acetate; metabolites were separated by high-performance liquid chromatography and identified by mass spectrometry and proton nuclear magnetic resonance spectroscopy. Flumequine was transformed to two diastereomers of 7-hydroxyflumequine (23 and 43% of the total chromatographic peak area at 280nm) and 7-oxoflumequine (11% of the total peak area). This is the first time that the two 7-hydroxy diastereomers have been characterized structurally; the hydroxyflumequines are known to have less antimicrobial activity than flumequine.
    Chemosphere 03/2007; 67(2):240-3. · 3.14 Impact Factor
  • Rapid Communications in Mass Spectrometry 04/2006; · 2.51 Impact Factor
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    Rapid Communications in Mass Spectrometry 03/2006; 20:595-603. · 2.51 Impact Factor
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    ABSTRACT: Circular dichroism (CD) and UV-melting experiments were conducted with 16 oligodeoxynucleotides modified by the carcinogen 2-aminofluorene, whose sequence around the lesion was varied systematically [d(CTTCTNG[AF]NCCTC), N = G, A, C, T], to gain insight into the factors that determine the equilibrium between base-displaced stacked (S) and external B-type (B) duplex conformers. Differing stabilities among the duplexes can be attributed to different populations of S and B conformers. The AF modification always resulted in sequence-dependent thermal (T(m)) and thermodynamic (-DeltaG degrees ) destabilization. The population of B-type conformers derived from eight selected duplexes (i.e. -AG*N- and -CG*N-) was inversely proportional to the -DeltaG degrees and T(m) values, which highlights the importance of carcinogen/base stacking in duplex stabilization even in the face of disrupted Watson-Crick base pairing in S-conformation. CD studies showed that the extent of the adduct-induced negative ellipticities in the 290-350 nm range is correlated linearly with -DeltaG degrees and T(m), but inversely with the population of B-type conformations. Taken together, these results revealed a unique interplay between the extent of carcinogenic interaction with neighboring base pairs and the thermodynamic properties of the AF-modified duplexes. The sequence-dependent S/B heterogeneities have important implications in understanding how arylamine-DNA adducts are recognized in nucleotide excision repair.
    Nucleic Acids Research 02/2006; 34(2):755-63. · 8.81 Impact Factor
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    ABSTRACT: Robust, specific, and rapid identification of toxic strains of bacteria and viruses, to guide the mitigation of their adverse health effects and optimum implementation of other response actions, remains a major analytical challenge. This need has driven the development of methods for classification of microorganisms using mass spectrometry, particularly matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), that allows high-throughput analyses with minimum sample preparation. We describe a novel approach to cell typing based on pattern recognition of MALDI mass spectra, which involves charge-state deconvolution in conjunction with a new correlation analysis procedure. The method is applicable to both prokaryotic and eukaryotic cells. Charge-state deconvolution improves the quantitative reproducibility of spectra because multiply charged ions resulting from the same biomarker attaching a different number of protons are recognized and their abundances are combined. This allows a clearer distinction of bacterial strains or of cancerous and normal liver cells. Improved class distinction provided by charge-state deconvolution was demonstrated by cluster spacing on canonical variate score charts and by correlation analyses. Deconvolution may enhance detection of early disease state or therapy progress markers in various tissues analyzed by MALDI-MS.
    Rapid Communications in Mass Spectrometry 02/2006; 20(10):1595-603. · 2.51 Impact Factor
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    ABSTRACT: The product ion formation characteristics of the protonated molecule ions generated from 10 different deoxynucleoside adducts of benzo[ghi]fluoranthene (B[ghi]F) have been studied using electrospray ionization (ESI) and quadrupole ion trap mass spectrometry to gain a better understanding of the fragmentation mechanisms that govern structure-specific fragmentation. The reaction of the syn- and anti-diastereomers of trans-3,4-dihydroxy-5,5a-tetrahydrobenzo[ghi]fluoranthene with DNA produce four deoxyguanosine, four deoxyadenosine, and two deoxycytidine adducts whose structures differ based on the cis/trans arrangement of the hydroxyl groups and nucleic acids bound to B[ghi]F. Those adducts that have structures where the nucleic acid and 3′-hydroxyl group of B[ghi]F are cis with respect to each other undergo extensive water loss whereas those isomers where the nucleic acid and 3′-hydroxyl group are trans do not. These results are consistent with a mechanism of water loss initiated by a hydrogen-bonding interaction between the charge-bearing proton on a heterocyclic nitrogen atom on the nucleic acid and the 3′-hydroxyl oxygen on the PAH. The dG and dC adducts are observed to undergo more extensive water loss than the dA adducts. Molecular modeling indicates that the larger relative abundances of the product ions formed by water loss for the dG and dC relative to dA are due to stronger hydrogen-bonding interactions prior to fragmentation and the greater stability of the carbocations formed at the C3′ carbon after fragmentation.
    Analytica Chimica Acta 01/2006; · 4.39 Impact Factor
  • M. Paul Chiarelli, Jackson O. Lay Jr
    Mass Spectrometry Reviews 02/2005; 11(6):447 - 493. · 7.74 Impact Factor
  • Pittsburgh Conference; 04/2004
  • Chemical Research in Toxicology - CHEM RES TOXICOL. 01/2004; 17(11):1549-1549.
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    ABSTRACT: Product ion spectra from thirteen C8-substituted alkylaniline adducts of guanine and deoxyguanosine were generated using electrospray ionization and quadrupole ion trap mass spectrometry and studied to investigate the possibility of differentiating isomeric adduct structures based upon the relative abundances of fragment ions derived from the alkylaniline-modified guanine bases (BH2(+) ions). The structural discrimination of the BH2(+) ions formed by attachment of isomeric alkylanilines to the C8 position of guanine is a challenging problem because the ions tend to yield product ion spectra that are qualitatively identical upon collisional activation. In this study, a statistical method, referred to as a similarity index, was used to compare the product ion spectra of isomeric BH2(+) ions and differentiate their structures. All the adducts investigated could be distinguished from SIs calculated using 5-6 product ions. These results suggest that a searchable database of product ion spectra may be created and used to characterize DNA adducts from aromatic amines whenever they are detected at levels amenable to mass spectral analysis.
    Journal of the American Society for Mass Spectrometry 01/2004; 14(12):1488-92. · 3.59 Impact Factor
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    ABSTRACT: The product ion formation characteristics of four diastereomeric deoxyadenosine adducts formed by the reaction of the syn and anti diastereomers of trans-3,4-dihydroxy-5,5a-epoxy-3,4,5,5a-tetrahydrobenzo[ghi]fluoranthene are studied by matrix-assisted laser desorption ionization and postsource decay (PSD) to determine fragmentation pathways that may permit differentiation of their structures. The two adducts derived from each diol-epoxide with DNA differ in structure based on the cis/trans arrangement of the 3'-hydroxyl group on the benzo[ghi]fluoranthene (B[ghi]F) and the adenine base bound to the B[ghi]F 5a carbon. The two adduct diastereomers with the cis adenine-3'-hydroxyl configuration produce product ions at m/z 394 and m/z 510 formed by the loss of water that are not observed in the PSD spectra of the two trans isomers. The data suggest a mechanism of water loss that is initiated by a hydrogen-bonding interaction between the charge-bearing proton on the N1 atom and the 3'-hydroxyl oxygen on the polycyclic aromatic hydrocarbon (PAH). Fragmentation is initiated by the transfer of the adenine N1 proton from the nitrogen to the PAH 3'-hydroxyl oxygen and inductive cleavage of the C3-O(3) bond to form a benzylic carbocation on B[ghi]F. The proposed mechanism is supported by semiempirical molecular modeling calculations.
    Chemical Research in Toxicology 11/2003; 16(10):1236-41. · 3.67 Impact Factor

Publication Stats

139 Citations
131.08 Total Impact Points

Institutions

  • 2002–2012
    • University of Rhode Island
      • Department of Biomedical and Pharmaceutical Sciences
      Kingston, RI, United States
  • 1999–2012
    • Loyola University Chicago
      • Department of Chemistry and Biochemistry
      Chicago, IL, United States
  • 1998
    • Loyola University
      • Chemistry
      New Orleans, Louisiana, United States
  • 1992–1994
    • University of Arkansas at Little Rock
      • Department of Chemistry
      Little Rock, Arkansas, United States