Reactive OFF-ON type alkylating agents for higher-ordered structures of nucleic acids

Area of Science:

• Chemical Biology
• Molecular Biology
• Biochemistry

Background:

• Higher-ordered nucleic acid structures (G-quadruplexes, mismatches, bulges) are crucial in genetic regulation and disease.
• Selective chemical modification of these structures is difficult due to reagent instability and off-target reactions.

Purpose of the Study:

• To develop novel alkylating agents for selective modification of higher-ordered nucleic acid structures.
• To control alkylation reactivity using an OFF-ON mechanism.

Main Methods:

• Design and synthesis of vinyl-quinazolinone (VQ) precursors with controllable reactivity.
• Conjugation of VQ precursors with aminoacridine for G-quadruplex DNA targeting.
• Testing the selectivity of VQ precursors against various nucleic acid structures (G-4 DNA, ssDNA, dsDNA, AP-site, G-4 RNA, T-T mismatch).

Main Results:

• VQ precursors with sulfoxide, thiophenyl, or thiomethyl groups demonstrated OFF-ON control of vinyl reactivity.
• Aminoacridine-conjugated VQ selectively alkylated thymine (T) bases in G-quadruplex DNA.
• VQ precursors also reacted with T or uracil (U) bases in AP-site, G-quadruplex RNA, and T-T mismatch structures.

Conclusions:

• Novel VQ precursors offer a new strategy for selective T or U alkylation in higher-ordered nucleic acid structures.
• These reagents have potential applications in studying nucleic acid functions and developing therapeutic strategies.