NDLI: A general strategy for target-promoted alkylation in biological systems

Content Provider	PubMed Central
Author	Zhou, Qibing Rokita, Steven E.
Copyright Year	2003
Abstract	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.
Related Links	http://dx.doi.org/10.1073/pnas.2533112100
Ending Page	15457
Page Count	6
Starting Page	15452
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	26
Volume Number	100
Language	English
Publisher	National Academy of Sciences
Publisher Date	2003-12-23
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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