Directing Quinone Methide-Dependent Alkylation and Cross-Linking of Nucleic Acids with Quaternary Amines
| Autor: | Steven E. Rokita, Sierra J. Williams, Shane R. Byrne, Mark A. Hutchinson, Blessing D. Deeyaa |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Alkylation
Biomedical Engineering DNA Single-Stranded Pharmaceutical Science Bioengineering 02 engineering and technology 01 natural sciences Article chemistry.chemical_compound Amines Indolequinones Pharmacology 010405 organic chemistry Chemistry Organic Chemistry DNA 021001 nanoscience & nanotechnology Combinatorial chemistry Quinone methide 0104 chemical sciences Kinetics Electrostatic attraction Reagent Nucleic acid Acridines 0210 nano-technology Polyamine Biotechnology Conjugate |
| Zdroj: | Bioconjug Chem |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/acs.bioconjchem.0c00166 |
| Popis: | Polyamine and polyammonium ion conjugates are often used to direct reagents to nucleic acids based on their strong electrostatic attraction to the phosphoribose backbone. Such non-specific interactions do not typically alter the specificity of the attached reagent, but polyammonium ions dramatically redirected the specificity of a series of quinone methide precursors. Replacement of a relatively non-specific intercalator based on acridine with a series of polyammonium ions resulted in a surprising change of DNA products. Piperidine stable adducts were generated in duplex DNA that lacked the ability to support a dynamic cross-linking observed previously with acridine conjugates. Minor reaction at guanine N7, the site of reversible reaction, was retained by a monofunctional quinone methide-polyammonium ion conjugate but a bisfunctional analogue designed for tandem quinone methide formation modified guanine N7 in only single-stranded DNA. The resulting intrastrand cross-links were sufficiently dynamic to rearrange to interstrand cross-links. However, no further transfer of adducts was observed in duplex DNA. An alternative design that spatially and temporally decoupled the two quinone methide equivalents neither restored the dynamic reaction nor cross-linked DNA efficiently. While di- and triammonium ion conjugates successfully enhanced the yields of cross-linking by a bisquinone methide relative to a monoammonium equivalent, alternative ligands will be necessary to facilitate the migration of cross-linking and its potential application to disrupt DNA repair. |
| Databáze: | OpenAIRE |
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