Michael addition-activated alkylation of G-quadruplex DNA with methylamine-protected vinyl-quinazolinone derivatives

Yutong Chen; Kazumitsu Onizuka; Fumi Nagatsugi

doi:10.1016/j.bmcl.2024.129855

Michael addition-activated alkylation of G-quadruplex DNA with methylamine-protected vinyl-quinazolinone derivatives

Bioorg Med Chem Lett. 2024 Sep 1:109:129855. doi: 10.1016/j.bmcl.2024.129855. Epub 2024 Jun 20.

Authors

Yutong Chen¹, Kazumitsu Onizuka², Fumi Nagatsugi³

Affiliations

¹ Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi 980-8577, Japan; Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan.
² Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi 980-8577, Japan; Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan; Division for the Establishment of Frontier Sciences of Organization for Advanced Studies, Tohoku University, Aoba-ku, Sendai, Miyagi 980-8577, Japan.
³ Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi 980-8577, Japan; Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan. Electronic address: fumi.nagatsugi.b8@tohoku.ac.jp.

PMID: 38908766
DOI: 10.1016/j.bmcl.2024.129855

Abstract

The role of G-quadruplex (G4) in cellular processes can be investigated by the covalent modification of G4-DNA using alkylating reagents. Controllable alkylating reagents activated by external stimuli can react elegantly and selectively. Herein, we report a chemical activation system that can significantly boost the reaction rate of methylamine-protected vinyl-quinazolinone (VQ) derivative for the alkylation of G4-DNA. The two screened activators can transform low-reactive VQ-NHR' to highly reactive intermediates following the Michael addition mechanism. This approach expands the toolbox of activable G4 alkylating reagents.

Keywords: Activation; Alkylation; DNA; G-quadruplex; Michael addition.

MeSH terms

Alkylation
DNA / chemistry
G-Quadruplexes* / drug effects
Humans
Methylamines* / chemical synthesis
Methylamines* / chemistry
Methylamines* / pharmacology
Molecular Structure
Quinazolinones* / chemical synthesis
Quinazolinones* / chemistry
Quinazolinones* / pharmacology
Vinyl Compounds / chemistry
Vinyl Compounds / pharmacology

Substances

Methylamines
Quinazolinones
methylamine
DNA
Vinyl Compounds