Design and synthesis of novel structures with anti-tumor effects: Targeting telomere G-quadruplex and hTERT

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Telomeres and the enzyme human telomerase reverse transcriptase (hTERT) are critical for cancer cell immortality.
• Targeting telomere maintenance mechanisms (TMMs) with small molecules offers a strategy to inhibit cancer proliferation.
• Telomeric G-quadruplex (G4) structures are key targets for anti-cancer drug development.

Purpose of the Study:

• To design and synthesize novel small molecule ligands that simultaneously target telomeric G-quadruplex (G4) and human telomerase reverse transcriptase (hTERT).
• To identify potent inhibitors capable of limiting cancer cell telomere lengthening and proliferation.
• To evaluate the anti-tumor potential and selectivity of the designed compounds.

Main Methods:

• Structure-activity relationship analysis of existing G4 stabilizers and hTERT inhibitors.
• Computational methods including molecular docking and quantitative structure-activity relationship (QSAR) for structure optimization.
• Synthesis of derivative compounds and in vitro evaluation of anti-tumor activity.
• Fluorescence experiments to assess selectivity for telomeric G4 over other DNA forms.
• Molecular dynamics simulations to verify compound-protein interactions.

Main Results:

• 144 candidate structures were designed based on SAR analysis.
• Compounds a16 and a35 were identified as optimal structures via molecular docking and mtQSAR.
• Synthesized derivatives b1-b6 were evaluated, with b4 demonstrating the most significant tumor cell inhibition.
• Compound b4 exhibited selective binding to telomeric G4 structures compared to single-stranded and double-stranded DNA.
• Molecular dynamics confirmed the stable interaction between b4 and hTERT.

Conclusions:

• The designed small molecules effectively target both telomeric G-quadruplex and hTERT.
• Compound b4 shows promising anti-tumor activity and selectivity, validating the dual-targeting strategy.
• This approach holds potential for developing novel cancer therapeutics targeting telomere maintenance.