Oligonucleotide Conjugates Derived from an Electrophilic Site: Conjugation to Baseless Carbohydrate Residue. Synthesis, Hybridization and Modeling Studies

Manoharan, Muthiah; Andrade, Laura K.; Mohan, V.; Freier, Susan M.; Cook, P. Dan

doi:10.1080/07328319708006267

Cited by 9 publications

(4 citation statements)

References 14 publications

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“…Literature precedents indicate that the amine-catalyzed β-elimination of acetate from 8 likely proceeds via iminium ion intermediates ( 9 and 10 , Scheme ). ,,,− We and others have used hydride reagents to trap iminium ion intermediates (e.g., 9 ) generated in the reactions of low-molecular-weight amines with AP sites in DNA. ,− ,,− To probe the involvement of iminium ion intermediates in the amine-catalyzed decomposition of 8 , we incubated the AP model compound with piperidine (30 mM) in the presence of the water-compatible hydride reagent NaBH 3 CN (4 equiv) . LC–MS analysis of the resulting reaction mixture revealed that the major peak in the UV and ion current chromatograms displayed an m / z of 484, consistent with the [M + H] + ion of the reduced iminium ion 13 (Scheme , Figure S1).…”

Section: Resultsmentioning

confidence: 99%

Products Generated by Amine-Catalyzed Strand Cleavage at Apurinic/Apyrimidinic Sites in DNA: New Insights from a Biomimetic Nucleoside Model System

Jha

Nel

Haldar

et al. 2022

Chem. Res. Toxicol.

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Abasic sites are common in cellular and synthetic DNA. As a result, it is important to characterize the chemical fate of these lesions. Amine-catalyzed strand cleavage at abasic sites in DNA is an important process in which conversion of small amounts of the ring-opened abasic aldehyde residue to an iminium ion facilitates β-elimination of the 3′-phosphoryl group. This reaction generates a trans-α,β-unsaturated iminium ion on the 3′-terminus of the strand break as an obligate intermediate. The canonical product expected from amine-catalyzed cleavage at an AP site is the corresponding trans-α,β-unsaturated aldehyde sugar remnant resulting from hydrolysis of this iminium ion. Interestingly, a handful of studies have reported noncanonical 3′-sugar remnants generated by amine-catalyzed strand cleavage, but the formation and properties of these products are not well-understood. To address this knowledge gap, a nucleoside system was developed that enabled chemical characterization of the sugar remnants generated by amine-catalyzed β-elimination in the 2-deoxyribose system. The results predict that amine-catalyzed strand cleavage at an AP site under physiological conditions has the potential to reversibly generate noncanonical cleavage products including cis-alkenal, 3-thio-2,3-dideoxyribose, and 2-deoxyribose groups alongside the canonical trans-alkenal residue on the 3′-terminus of the strand break. Thus, the model reactions provide evidence that the products generated by amine-catalyzed strand cleavage at abasic sites in cellular DNA may be more complex that commonly thought, with trans-α,β-unsaturated iminium ion intermediates residing at the hub of interconverting product mixtures. The results expand the list of possible 3′-sugar remnants arising from amine-catalyzed cleavage of abasic sites in DNA that must be chemically or enzymatically removed for the completion of base excision repair and single-strand break repair in cells.

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Section: Resultsmentioning

confidence: 99%

Products Generated by Amine-Catalyzed Strand Cleavage at Apurinic/Apyrimidinic Sites in DNA: New Insights from a Biomimetic Nucleoside Model System

Jha

Nel

Haldar

et al. 2022

Chem. Res. Toxicol.

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“…In this process, the reaction of the AP aldehyde with an amine yields an iminium ion intermediate that is selectively reduced by a hydride reagent to yield a chemically stable alkylamine or arylamine attachment to the deoxyribose backbone (Scheme ). ,− This reaction has been widely employed in mechanistic studies of amine-catalyzed strand cleavage at AP sites in DNA − but, perhaps surprisingly, has seen limited use for derivatization or targeted modification of DNA. ,,− ,− In the present studies, reductive amination reactions involving the AP aldehyde residues in DNA were carried out by incubation of AP-containing oligodeoxynucleotides with amine-containing linkers in the presence of the water-compatible hydride reducing agent NaBH 3 CN. , …”

Section: Results and Discussionmentioning

confidence: 99%

Synthesis of DNA Duplexes Containing Site-Specific Interstrand Cross-Links via Sequential Reductive Amination Reactions Involving Diamine Linkers and Abasic Sites on Complementary Oligodeoxynucleotides

Housh

Gates

2021

Chem. Res. Toxicol.

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Interstrand DNA cross-links are important in biology, medicinal chemistry, and materials science. Accordingly, methods for the targeted installation of interstrand cross-links in DNA duplexes may be useful in diverse fields. Here, a simple procedure is reported for the preparation of DNA duplexes containing site-specific, chemically defined interstrand cross-links. The approach involves sequential reductive amination reactions between diamine linkers and two abasic (apurinic/apyrimidinic, AP) sites on complementary oligodeoxynucleotides. Use of the symmetrical triamine, tris(2-aminoethyl)amine, in this reaction sequence enabled the preparation of a cross-linked DNA duplex bearing a derivatizable aminoethyl group.

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“…In the study, 90 the electrophilic centres of oligonucleotides were generated enzymatically: the uracil residues were cut off from the oligonucleotide chain using uracil ± DNA glycosylase to obtain the apurine/apyrimidine fragments. This was followed by modification of the aldehyde-containing oligonucleotides by various ligands carrying an amino group.…”

Section: Synthesis Of Conjugates Using a Carbonyl Derivative Of One O...mentioning

confidence: 99%

Modern methods for the synthesis of peptide–oligonucleotide conjugates

Zubin¹,

Романова²,

Oretskaya³

2002

Russ. Chem. Rev.

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The published data on the methods of chemical solution The published data on the methods of chemical solution and solid-phase synthesis of peptide ± oligonucleotide conjugates and solid-phase synthesis of peptide ± oligonucleotide conjugates are reviewed. The known methods are systematised and their are reviewed. The known methods are systematised and their advantages and disadvantages are considered. The approaches to advantages and disadvantages are considered. The approaches to the solution synthesis of peptide ± oligonucleotide conjugates are the solution synthesis of peptide ± oligonucleotide conjugates are systematised according to the type of chemical bonds between the systematised according to the type of chemical bonds between the fragments, whereas those to the solid-phase synthesis are classified fragments, whereas those to the solid-phase synthesis are classified according to the procedure used for the preparation of conjugates, according to the procedure used for the preparation of conjugates, viz viz., stepwise elongation of oligonucleotide and peptide chains on ., stepwise elongation of oligonucleotide and peptide chains on the same polymeric support or solid-phase condensation of two the same polymeric support or solid-phase condensation of two presynthesised fragments. The bibliography includes 141 referen-presynthesised fragments. The bibliography includes 141 references ces. .

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Oligonucleotide Conjugates Derived from an Electrophilic Site: Conjugation to Baseless Carbohydrate Residue. Synthesis, Hybridization and Modeling Studies

Cited by 9 publications

References 14 publications

Products Generated by Amine-Catalyzed Strand Cleavage at Apurinic/Apyrimidinic Sites in DNA: New Insights from a Biomimetic Nucleoside Model System

Products Generated by Amine-Catalyzed Strand Cleavage at Apurinic/Apyrimidinic Sites in DNA: New Insights from a Biomimetic Nucleoside Model System

Synthesis of DNA Duplexes Containing Site-Specific Interstrand Cross-Links via Sequential Reductive Amination Reactions Involving Diamine Linkers and Abasic Sites on Complementary Oligodeoxynucleotides

Modern methods for the synthesis of peptide–oligonucleotide conjugates

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