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Simplified synthesis of individual stereoisomers of the 4-hydroxynonenal adducts of deoxyguanosine.

ABSTRACT: We previously reported the synthesis of the 1,N(2)-deoxyguanosine adducts of 4-hydroxynonenal, an important product of lipid peroxidation, which involved the nucleophilic aromatic substitution reaction of an O(6)-protected-2-fluoroinosine with 4-amino-1,2,5-trihydroxydecanal followed by periodate oxidation of the vicinal diol.(3) An improved synthesis of the amino triols has been developed. The syn and anti diasteromers of a key intermediate, 4-nitro-5-hydroxy-1-decene, were synthesized by a Henry reaction and separated; each diastereomer was further separated into individual enantiomers by chiral supercritical fluid chromatography. Of note, dihydroxylation of the terminal olefin under conventional conditions with catalytic OsO4 and a tertiary amine oxide as the stoichiometric oxidant led to scrambling of stereochemistry at C4. The scrambling was not observed when t-butylhydroperoxide was used as the oxidant.

SUBMITTER: Christov PP

PROVIDER: S-EPMC3735235 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Simplified synthesis of individual stereoisomers of the 4-hydroxynonenal adducts of deoxyguanosine.

Christov Plamen P PP Hawkins Edward K EK Kett Nathan R NR Rizzo Carmelo J CJ

Tetrahedron letters 20130801 32

We previously reported the synthesis of the 1,N2-deoxyguanosine adducts of 4-hydroxynonenal, an important product of lipid peroxidation, which involved the nucleophilic aromatic substitution reaction of an O6-protected-2-fluoroinosine with 4-amino-1,2,5-trihydroxydecanal followed by periodate oxidation of the vicinal diol.3 An improved synthesis of the amino triols has been developed. The syn and anti diasteromers of a key intermediate ...[more]

PMID: 23935223

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Project description:The trans-4-hydroxynonenal (HNE)-derived exocyclic 1, N(2)-dG adduct with (6S,8R,11S) stereochemistry forms interstrand N(2)-dG-N(2)-dG cross-links in the 5'-CpG-3' DNA sequence context, but the corresponding adduct possessing (6R,8S,11R) stereochemistry does not. Both exist primarily as diastereomeric cyclic hemiacetals when placed into duplex DNA [Huang, H., Wang, H., Qi, N., Kozekova, A., Rizzo, C. J., and Stone, M. P. (2008) J. Am. Chem. Soc. 130, 10898-10906]. To explore the structural basis for this difference, the HNE-derived diastereomeric (6S,8R,11S) and (6R,8S,11R) cyclic hemiacetals were examined with respect to conformation when incorporated into 5'-d(GCTAGC XAGTCC)-3' x 5'-d(GGACTCGCTAGC)-3', containing the 5'-CpX-3' sequence [X = (6S,8R,11S)- or (6R,8S,11R)-HNE-dG]. At neutral pH, both adducts exhibited minimal structural perturbations to the DNA duplex that were localized to the site of the adduction at X(7) x C(18) and its neighboring base pair, A(8) x T(17). Both the (6S,8R,11S) and (6R,8S,11R) cyclic hemiacetals were located within the minor groove of the duplex. However, the respective orientations of the two cyclic hemiacetals within the minor groove were dependent upon (6S) versus (6R) stereochemistry. The (6S,8R,11S) cyclic hemiacetal was oriented in the 5'-direction, while the (6R,8S,11R) cyclic hemiacetal was oriented in the 3'-direction. These cyclic hemiacetals effectively mask the reactive aldehydes necessary for initiation of interstrand cross-link formation. From the refined structures of the two cyclic hemiacetals, the conformations of the corresponding diastereomeric aldehydes were predicted, using molecular mechanics calculations. Potential energy minimizations of the duplexes containing the two diastereomeric aldehydes predicted that the (6S,8R,11S) aldehyde was oriented in the 5'-direction while the (6R,8S,11R) aldehyde was oriented in the 3'-direction. These stereochemical differences in orientation suggest a kinetic basis that explains, in part, why the (6S,8R,11S) stereoisomer forms interchain cross-links in the 5'-CpG-3' sequence whereas the (6R,8S,11R) stereoisomer does not.

Project description:The alpha,beta-unsaturated aldehydes (enals) acrolein, crotonaldehyde, and trans-4-hydroxynonenal (4-HNE) are products of endogenous lipid peroxidation, arising as a consequence of oxidative stress. The addition of enals to dG involves Michael addition of the N(2)-amine to give N(2)-(3-oxopropyl)-dG adducts, followed by reversible cyclization of N1 with the aldehyde, yielding 1,N(2)-dG exocyclic products. The 1,N(2)-dG exocyclic adducts from acrolein, crotonaldehyde, and 4-HNE exist in human and rodent DNA. The enal-induced 1,N(2)-dG lesions are repaired by the nucleotide excision repair pathway in both Escherichia coli and mammalian cells. Oligodeoxynucleotides containing structurally defined 1,N(2)-dG adducts of acrolein, crotonaldehyde, and 4-HNE were synthesized via a postsynthetic modification strategy. Site-specific mutagenesis of enal adducts has been carried out in E. coli and various mammalian cells. In all cases, the predominant mutations observed are G-->T transversions, but these adducts are not strongly miscoding. When placed into duplex DNA opposite dC, the 1,N(2)-dG exocyclic lesions undergo ring opening to the corresponding N(2)-(3-oxopropyl)-dG derivatives. Significantly, this places a reactive aldehyde in the minor groove of DNA, and the adducted base possesses a modestly perturbed Watson-Crick face. Replication bypass studies in vitro indicate that DNA synthesis past the ring-opened lesions can be catalyzed by pol eta, pol iota, and pol kappa. It also can be accomplished by a combination of Rev1 and pol zeta acting sequentially. However, efficient nucleotide insertion opposite the 1,N(2)-dG ring-closed adducts can be carried out only by pol iota and Rev1, two DNA polymerases that do not rely on the Watson-Crick pairing to recognize the template base. The N(2)-(3-oxopropyl)-dG adducts can undergo further chemistry, forming interstrand DNA cross-links in the 5'-CpG-3' sequence, intrastrand DNA cross-links, or DNA-protein conjugates. NMR and mass spectrometric analyses indicate that the DNA interstand cross-links contain a mixture of carbinolamine and Schiff base, with the carbinolamine forms of the linkages predominating in duplex DNA. The reduced derivatives of the enal-mediated N(2)-dG:N(2)-dG interstrand cross-links can be processed in mammalian cells by a mechanism not requiring homologous recombination. Mutations are rarely generated during processing of these cross-links. In contrast, the reduced acrolein-mediated N(2)-dG peptide conjugates can be more mutagenic than the corresponding monoadduct. DNA polymerases of the DinB family, pol IV in E. coli and pol kappa in human, are implicated in error-free bypass of model acrolein-mediated N(2)-dG secondary adducts, the interstrand cross-links, and the peptide conjugates.

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Simplified synthesis of individual stereoisomers of the 4-hydroxynonenal adducts of deoxyguanosine.

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Simplified synthesis of individual stereoisomers of the 4-hydroxynonenal adducts of deoxyguanosine.

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