Enhanced G-Quadruplex Stability and Anticancer Activity of N²-Aryl Deoxyguanosine-Modified T40214 Oligonucleotides...

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Signal transducer and activator of transcription 3 (Stat3) is crucial for cancer cell proliferation and survival, making it a key therapeutic target.
• G-quadruplex (G4) forming oligonucleotides, like T40214, can inhibit Stat3 DNA binding activity.
• Developing novel Stat3 inhibitors is essential for advancing prostate cancer treatment.

Purpose of the Study:

• To synthesize and characterize novel T40214 derivatives with N2-furfuryl and N2-cinnamyl modifications at G-tetrad positions.
• To evaluate the structural integrity, thermal stability, and Stat3 interaction of these modified G4 oligonucleotides.
• To assess the in vitro antitumor efficacy, including antiproliferative and pro-apoptotic effects, in prostate cancer cells.

Main Methods:

• Chemical synthesis of N2-furfuryl and N2-cinnamyl modified deoxyguanosine.
• Structural analysis using gel mobility assays and molecular dynamics simulations.
• Antiproliferative and apoptosis assays in DU145 prostate cancer cells, along with gene expression analysis.

Main Results:

• Single N2-aryl modifications maintained the parallel G4 conformation.
• TF15 and TC15 modifications significantly enhanced thermal stability and were well-accommodated at the 5'-ends.
• Aryl-modified T40214 derivatives formed stable 5'-5' dimers and demonstrated potent antiproliferative activity (IC50 = 0.37-0.39 μM) and apoptosis induction.
• TF15 and TC15 suppressed Stat3-mediated gene expression in DU145 cells.

Conclusions:

• N2-aryl modifications in T40214 G4 oligonucleotides enhance structural stability and antitumor potency.
• TF15 and TC15 represent promising Stat3-targeting agents for prostate cancer therapy.
• These findings support the development of modified G4 oligonucleotides as a novel therapeutic strategy for Stat3-driven cancers.