DNA alkylation promoted by an electron-rich quinone methide intermediate

Abstract

Biological application of conjugates derived from oligonucleotides and quinone methides have previously been limited by the slow exchange of their covalent self-adducts and subsequent alkylation of target nucleic acids. To enhance the rates of these processes, a new quinone methide precursor with an electron donating substituent has been prepared. Additionally, this substituent has been placed para to the nascent exo-methylene group of the quinone methide for maximum effect. A conjugate made from this precursor and a 5'-aminohexyloligonucleotide accelerates formation of its reversible self-adduct and alkylation of its complementary DNA as predicted from prior model studies.

Graphical abstract

Keywords

quione methide / DNA alkylation / reversible covalent reaction / bioconjugation / target-directed modification of nucleic acids

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Acknowledgment

We thank Lyle Isaacs for his suggestions on QMP design and the NIH (CA81571) for partial support of this project. The authors declare no competing financial interests.

Electronic Supplementary Material

ƒSupplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s11705-015-1541-3 and is accessible for authorized users.

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