Hydrosoluble Perylene Monoimide-Based Telomerase Inhibitors with Diminished Cytotoxicity

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Molecular Pharmacology

Background:

• Telomerase is crucial for cancer cell immortality.
• Perylene-based G-quadruplex (G4) ligands are investigated as telomerase inhibitors.
• Perylene diimides (PDIs) often aggregate in aqueous solutions, limiting their use.

Purpose of the Study:

• To develop novel perylene monoimide (PMI) derivatives with improved drug-like properties for telomerase inhibition.
• To assess the impact of specific side chain modifications on cytotoxicity, solubility, G4 binding, and telomerase inhibition.
• To identify PMIs with selective telomerase inhibition and reduced toxicity in cancer cells.

Main Methods:

• Synthesis of novel asymmetric PMIs (PM3 and PM5) by modifying side chains of a known PMI (PM2).
• Evaluation of hydrosolubility, G4 binding affinity, and in vitro telomerase inhibition.
• Assessment of cytotoxicity in three cancer cell lines and suppression of human telomerase reverse transcriptase (hTERT) expression and activity in A549 cells.

Main Results:

• PMIs (PM2, PM3, PM5) demonstrated superior hydrosolubility, G4 binding, and in vitro telomerase inhibition compared to the prototypic PDI (PIPER).
• PM5 showed significantly reduced cytotoxicity (7-10 times less) compared to PM2 and PM3 in tested cancer cell lines.
• PM5 effectively suppressed hTERT expression and telomerase activity in A549 cells without increased toxicity.

Conclusions:

• Replacing the N,N-diethylethylenediamine side chain with 2-aminoethylpiperidine in PMIs reduces cytotoxicity without compromising G4 binding or telomerase inhibition.
• Asymmetric PMIs with basic side chains are effective telomerase inhibitors with improved properties over PDIs.
• This research provides a foundation for designing new PMIs with enhanced drug-like characteristics for selective telomerase inhibition in cancer therapy.