Core-Extended Naphthalene Diimide Dyads as Light-Up Probes with Targeted Cytotoxicity Toward Tumor Cells

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biotechnology

Background:

• Rational drug design requires specific molecular targeting for cancer therapy.
• G-quadruplex (G4) ligands, such as naphthalene diimide (NDI) and core-extended NDI (ceNDI), are explored for their potential in cancer treatment and diagnostics.
• ceNDI's red emission offers diagnostic capabilities, but its binding affinity and selectivity need enhancement.

Purpose of the Study:

• To design and synthesize novel NDI-ceNDI dyads to improve binding affinity and target selectivity for cancer cells.
• To evaluate the diagnostic and therapeutic potential of these dyads as theranostic agents.
• To investigate the role of different linkers in determining target selectivity and therapeutic efficacy.

Main Methods:

• Synthesis of NDI-ceNDI dyads with varying linkers.
• Characterization of DNA binding affinity using binding constants and DNA-binding assays.
• Assessment of fluorescence turn-on response upon DNA recognition.
• Analysis of induced circular dichroism signals to determine DNA conformation.
• Evaluation of cytotoxicity on cancer cell lines and normal cells.
• Investigation of selective DNA damage induction in transformed cells.

Main Results:

• NDI-ceNDI dyads exhibit fluorescence turn-on and induce circular dichroism signals dependent on DNA conformation.
• Both dyads show high affinity for hybrid G4 structures, with binding constants significantly higher than for double-stranded DNA.
• The dyad with a rigid triazole linker demonstrates selective induction of DNA damage in cancer cells, sparing normal cells.
• High cytotoxicity was observed in cancer cell lines, indicating therapeutic potential.

Conclusions:

• NDI-ceNDI dyads are effective G4 ligands and fluorescent probes with potential as theranostic agents.
• The linker's rigidity plays a crucial role in achieving selective DNA damage in cancer cells.
• This approach offers promising insights for developing precision medicine strategies targeting cancer-specific DNA structures.