Dual functional dinuclear platinum complex with selective reactivity towards c-myc G-quadruplex

Area of Science:

• Medicinal Chemistry
• Supramolecular Chemistry
• Oncology

Background:

• G-quadruplexes (GQ) are promising anticancer targets due to their role in oncogenic G-rich sequences.
• Current therapeutic strategies primarily use non-covalent binders, leaving covalent targeting underexplored.

Purpose of the Study:

• To design and synthesize novel dinuclear platinum complexes for covalent targeting of G-quadruplexes.
• To investigate the dual-functional binding mechanism of these complexes to G-quadruplex structures.

Main Methods:

• Synthesis of dinuclear platinum complexes with varying alkyl linkages.
• Characterization of platinum complexes and their binding interactions with G-quadruplexes.
• Evaluation of the specificity towards c-myc G-quadruplex.

Main Results:

• A series of dinuclear platinum complexes, specifically Pt3 with a nonanediamine linkage, demonstrated optimized binding to the c-myc G-quadruplex.
• The complexes exhibit a dual-functional binding mode: non-covalent π-stacking by aromatic ligands and covalent chelation by Pt(II) cores.
• Covalent chelation occurred at both 3'- and 5'-ends of the guanines within the G-quadruplex structure.

Conclusions:

• Dinuclear platinum complexes represent a novel covalent strategy for targeting G-quadruplexes.
• The designed complexes show potential as anticancer therapeutics by specifically binding and stabilizing oncogenic G-quadruplex structures.