Exploring copper(I) as a catalyst for nucleic acid alkylation

Geigle, Stefanie N.. Exploring copper(I) as a catalyst for nucleic acid alkylation. 2017, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_12658

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Chemical manipulations of nucleic acids have been crucial in the development of methodologies to study and understand epigenetics and transcriptomes. However, a complete understanding of these complex and dynamic systems is still missing and therefore we believe new synthetic tools for selective nucleic acid engineering are required. We report here the discovery that copper(I) carbenes derived from α-diazocarbonyl compounds selectively alkylate the O6-position of guanine (O6-G) in mono- and oligonucleotides. This new methodology allows the targeting of only purine-type lactam oxygen, whereas other types of amides or lactams are poorly reactive under the smooth guanine alkylation conditions. Mechanistic studies point to a substrate-directed alkylation reaction with the N7G as the key functionality of the purine-nucleobase that controls the high chemoselectivity. We used copper(I)-catalyzed O6-G alkylation to readily engineer O6-G derivatives to study two open questions in the biochemistry of O6-G adducts: the repair by alkylguanine transferases and their incorporation efficiency during DNA replication. Furthermore, with a reactivity and stability screen of functionalized water soluble N-heterocyclic carbene ligands we could identify tight-binding variants that permanently stabilized copper(I) in water. This system allowed alkylation of oligonucleotides in a reducing agent free environment maintaining the selectivity for the O6-G position. Most importantly, the tight-binding ligands that stabilize copper(I) provide access to further functionalization such as bio-conjugation. Given the importance of O6-G lesion in biology and the need for simple methods to engineer nucleic acids, we believe that copper(I)-catalyzed O6-G alkylation will find broad applicability.
Advisors:Seebeck, Florian Peter and Gillingham, Dennis G.
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Organische Chemie (Gillingham)
UniBasel Contributors:Seebeck, Florian Peter and Gillingham, Dennis
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12658
Thesis status:Complete
Number of Pages:1 Online-Ressource (xi, 135 Seiten)
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edoc DOI:
Last Modified:04 Jul 2018 04:30
Deposited On:28 Jun 2018 07:56

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