Synthesis of the minor acrolein adducts of 2′-deoxyguanosine and their generation in oligomeric DNA

Huang, Yanhe; Torres, Maria Cecilia de Araujo Rodrigues; Iden, Charles R.; Johnson, Francis

doi:10.1016/s0045-2068(02)00525-4

Cited by 14 publications

(15 citation statements)

References 16 publications

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“…The oligomer containing the lesion was prepared using standard solid-phase synthesis methods, following a postsynthetic procedure for the incorporation of α-OH-PdG (20). Briefly, the 5′- O -dimethoxytrityl-3′- O -(β-cyanoethyl)-phosphoramidite derivative of 1-(3,4-diacetylbutyl)- N 2 -(dimethylaminomethylene)-dG was chemically synthesized and used to incorporate 1-(3,4-diacetoxybutyl)-dG at the center of an undecanucleotide.…”

Section: Methodsmentioning

confidence: 99%

Solution structure of DNA containing α-OH-PdG: the mutagenic adduct produced by acrolein

Zaliznyak¹,

Bonala²,

Attaluri³

et al. 2009

Nucleic Acids Research

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Acrolein is a cell metabolic product and a main component of cigarette smoke. Its reaction with DNA produces two guanine lesions γ-OH-PdG, a major adduct that is nonmutagenic in mammalian cells, and the positional isomer α-OH-PdG. We describe here the solution structure of a short DNA duplex containing a single α-OH-PdG lesion, as determined by solution NMR spectroscopy and restrained molecular dynamics simulations. The spectroscopic data show a mostly regular right-handed helix, locally perturbed at its center by the presence of the lesion. All undamaged residues of the duplex are in anti orientation, forming standard Watson–Crick base-pair alignments. Duplication of proton signals near the damaged site differentiates two enantiomeric duplexes, thus establishing the exocyclic nature of the lesion. At the lesion site, α-OH-PdG rotates to a syn conformation, pairing to its counter cytosine residue that is protonated at pH 5.9. Three-dimensional models produced by restrained molecular dynamics simulations show different hydrogen-bonding patterns between the lesion and its cytosine partner and identify further stabilization of α-OH-PdG in a syn conformation by intra-residue hydrogen bonds. We compare the α-OH-PdG•dC duplex structure with that of duplexes containing the analogous lesion propano-dG and discuss the implications of our findings for the mutagenic bypass of acrolein lesions.

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Section: Methodsmentioning

confidence: 99%

Solution structure of DNA containing α-OH-PdG: the mutagenic adduct produced by acrolein

Zaliznyak¹,

Bonala²,

Attaluri³

et al. 2009

Nucleic Acids Research

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Section: Synthesis Of Oligodeoxynucleotides Containing 1n 2 -Dg Enalmentioning

confidence: 99%

“…[49][50][51][52] This strategy could not be applied to oligodeoxynucleotides containing α-OH-PdG (10), which were prepared using the modified phosphoramidite 25. 53,54 Interstrand Cross-linking by γ-OH-PdGOligodeoxynucleotide 30, containingγ-OH-PdG adduct 9, was annealed to its complement and the formation of an interstrand cross-link was monitored by capillary gel electrophoresis (CGE) (Figure 3). 55,56 A new species formed and reached a level of ~ 50% yield after seven days at 25 °C.…”

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confidence: 99%

Interstrand DNA Cross-Links Induced by α,β-Unsaturated Aldehydes Derived from Lipid Peroxidation and Environmental Sources

et al. 2008

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ConspectusSignificant levels of the 1,N 2 -γ-hydroxypropano-dG adducts of the α,β-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxy-2E-nonenal (HNE) have been identified in human DNA, arising from both exogenous and endogenous exposure. They yield interstrand DNA cross-links between guanines in the neighboring C•G and G•C base pairs located in 5′-CpG-3′ sequences, as a result of opening of the 1,N 2 -γ-hydroxypropano-dG adducts to form reactive aldehydes that are positioned within the minor groove of duplex DNA. Using a combination of chemical, spectroscopic, and computational methods, we have elucidated the chemistry of cross-link formation in duplex DNA. NMR spectroscopy revealed that, at equilibrium, the acrolein and crotonaldehyde cross-links consist primarily of interstrand carbinolamine linkages between the exocyclic amines of the two guanines located in the neighboring C•G and G•C base pairs located in 5′-CpG-3′ sequences, that maintain the Watson-Crick hydrogen bonding of the cross-linked base pairs. The ability of crotonaldehyde and HNE to form interstrand cross-links depends upon their common relative stereochemistry at the C6 position of the 1,N 2 -γ-hydroxypropano-dG adduct. The stereochemistry at this center modulates the orientation of the reactive aldehyde within the minor groove of the doublestranded DNA, either facilitating or hindering the cross-linking reactions; it also affects the stabilities of the resulting diastereoisomeric cross-links. The presence of these cross-links in vivo is anticipated to interfere with DNA replication and transcription, thereby contributing to the etiology of human disease. Reduced derivatives of these cross-links are useful tools for studying their biological processing. IntroductionThe α,β-unsaturated aldehydes (enals) acrolein, crotonaldehyde, and 4-hydroxynonenal (4-HNE) (Scheme 1) are endogenous byproducts of lipid peroxidation, arising as a consequence of oxidative stress. [1][2][3][4] Acrolein and crotonaldehyde exposures also occur from exogenous sources, e.g., cigarette smoke 5 and automobile exhaust. 6 Enals react with DNA nucleobases to give exocyclic adducts; they also react with proteins. 7 Addition of enals to dG involves Michael addition of the N 2 -amine to give N 2 -(3-oxopropyl)-dG adducts (1, 3-8), followed by * Michael P. Stone telephone, 615-322-2589; fax, 615-322-7591; michael.p The lipid peroxidation product 4-HNE afforded related dGadducts (13-16). 14 Identification of acrolein adducts of other nucleosides followed. 15,16 The principal acrolein adduct is γ-OH-PdG (9), 10,12 although the regioisomeric 6-hydroxypyrimido[1,2-a]purin-10(3H)-one (α-OH-PdG, 10) has also been observed. 12,17 The γ-OH-PdG adduct (9) exists as a mixture of C8-OH epimers. With crotonaldehyde, addition at N 2 -dG creates a stereocenter at C6. Of four possible products, the two with the trans relative configurations at C6 and C8 (11,12) are observed. 12,18 These are also formed through the reaction of dG with two equivalents of acetaldehyde. 5,19,20 The cor...

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“…Condensation of 24 with the phosphoramidite 16 in the presence of 1H-tetrazole, followed by hydrogen peroxide workup, gave the phosphotriester 25 in 80 % yield. At this stage the 3Ј-hydroxy group was unmasked by treatment with HF·pyridine [36] to afford 26 in 69 % yield. The final deprotection of the phosphate group was effected by treatment with a large excess of triethylamine in acetonitrile to give the triethylammonium phosphate salt 5a in 98 % yield as an amorphous white solid.…”

Section: Resultsmentioning

confidence: 99%

Squalenoyl Gemcitabine Monophosphate: Synthesis, Characterisation of Nanoassemblies and Biological Evaluation

et al. 2011

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Trialkylammonium 4-(N)-1,1Ј,2-trisnor-squalenoylgemcitabine monophosphate (SQdFdC-MP) salts were prepared from 1,1Ј,2-trisnor-squalenoylgemcitabine by phosphoramiditetype chemistry. This amphiphilic molecule self-assembled into nanoassemblies of about 100 nm in size in aqueous solutions. Cryo-TEM and small-angle X-ray scattering (SAXS) investigations revealed that SQdFdC-MP molecules selforganized into unilamellar liposomes with a membrane

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Synthesis of the minor acrolein adducts of 2′-deoxyguanosine and their generation in oligomeric DNA

Cited by 14 publications

References 16 publications

Solution structure of DNA containing α-OH-PdG: the mutagenic adduct produced by acrolein

Solution structure of DNA containing α-OH-PdG: the mutagenic adduct produced by acrolein

Interstrand DNA Cross-Links Induced by α,β-Unsaturated Aldehydes Derived from Lipid Peroxidation and Environmental Sources

Squalenoyl Gemcitabine Monophosphate: Synthesis, Characterisation of Nanoassemblies and Biological Evaluation

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