Recognition of G-quadruplex DNA by triangular star-shaped compounds: with or without side chains?

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Molecular Recognition

Background:

• Quadruplex DNA structures are increasingly recognized as important therapeutic targets.
• Developing small molecules for selective quadruplex binding is a key area of drug discovery.
• Triangular aromatic platforms offer a unique scaffold for designing DNA-binding agents.

Purpose of the Study:

• To synthesize and characterize two new series of triangular aromatic platforms: trisubstituted triazatrinaphthylenes (TrisK) and nonsubstituted triazoniatrinaphthylene (TrisQ).
• To evaluate the quadruplex DNA binding affinity and selectivity of these compounds.
• To compare the binding behavior of TrisK and TrisQ, focusing on the role of cationic charge localization and side chain modifications.

Main Methods:

• Synthesis of TrisK and TrisQ compounds.
• FRET-melting assays to determine quadruplex DNA binding affinity (ΔT(1/2)).
• G4-FID assays to assess quadruplex selectivity against duplex DNA.
• Structural considerations using the c-myc quadruplex model.

Main Results:

• TrisK compounds showed significant quadruplex affinity, with affinity influenced by substituent length and terminal NH(2) groups (up to ΔT(1/2)=20 °C).
• The nonsubstituted TrisQ exhibited higher quadruplex affinity (ΔT(1/2)=26 °C) and selectivity than the best TrisK candidate.
• Both TrisK3-NH and TrisQ showed favorable stacking interactions with the c-myc quadruplex G-quartet, potentially involving hydrogen bonding.

Conclusions:

• The nonsubstituted TrisQ is a highly promising novel molecular design for quadruplex DNA recognition.
• TrisQ displays binding characteristics comparable to established quadruplex binders like BRACO-19 and 360A.
• Modifications to triangular aromatic platforms can be tuned to optimize quadruplex binding affinity and selectivity.