A General Strategy for Target-Promoted Alkylation in Biological Systems

Selective alkylation of a chosen sequence of DNA typically relies on ligand-directed delivery of a compound that expresses an intrinsic reactivity. A significant and biologically relevant enhancement in specificity is theoretically possible if such an intrinsic reactivity could be replaced by a late...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 100; no. 26; pp. 15452 - 15457
Main Authors Zhou, Qibing, Rokita, Steven E.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 23.12.2003
National Acad Sciences
Subjects
Adducts
Alkylates
Alkylation
Base Sequence
Benzoquinones
Biochemistry
Biological Sciences
Deoxyribonucleic acid
DNA
DNA - chemistry
DNA Adducts - chemistry
Nucleic Acid Conformation
Nucleic acids
Nucleophiles
Oligodeoxyribonucleotides - chemistry
Oligonucleotides
Proteins
quinone methide
Quinones
Reactivity
Thiols
Trapping
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Summary:Selective alkylation of a chosen sequence of DNA typically relies on ligand-directed delivery of a compound that expresses an intrinsic reactivity. A significant and biologically relevant enhancement in specificity is theoretically possible if such an intrinsic reactivity could be replaced by a latent activity induced solely by the target of interest, but examples of this are rare and not easily emulated. A simple strategy for target-promoted alkylation is now illustrated by an intramolecular adduct formed by an oligonucleotide-quinone methide conjugate. This adduct persists in the absence of a complementary sequence of DNA for at least 8 days, yet remarkably is able to alkylate target DNA upon duplex hybridization. Neither formation of the intramolecular self-adduct nor transfer of the quinone methide to its target is significantly quenched by 450-fold excess 2-mercaptoethanol. Similarly, noncomplementary DNA is neither subject to alkylation by the self-adduct nor able to effect its consumption. Reversible trapping of the nascent quinone methide through an intramolecular reaction thus appears efficient enough to inhibit competing intermolecular reaction. Only complementary base pairing induces a conformational change necessary to promote intermolecular transfer of the quinone methide. Generalization of this approach based on reversible intramolecular trapping of a reactive intermediate by a ligand with multiple recognition subdomains has the potential for wide-ranging applications in targeting nucleic acids and proteins.
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To whom correspondence should be addressed. E-mail: rokita@umd.edu.
Present address: Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23284.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: QMP, quinone methide precursor; QM, ortho-benzoquinone methide; ESI, electrospray ionization.
Edited by Peter B. Dervan, California Institute of Technology, Pasadena, CA, and approved October 13, 2003
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2533112100