1,2,3-Triazole-totarol conjugates as potent PIP5K1α lipid kinase inhibitors

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Enzyme Inhibition

Background:

• Prostate cancer development is linked to the enzyme human phosphatidylinositol 4-phosphate 5-kinase type I α (hPIP5K1α).
• Natural products, like diterpene totarol, serve as scaffolds for developing novel therapeutic agents.

Purpose of the Study:

• To synthesize novel totarol derivatives and evaluate their inhibitory activity against hPIP5K1α.
• To assess the antiproliferative effects of the synthesized compounds on prostate cancer cell lines.

Main Methods:

• Seventeen O-propargylated totarol derivatives were synthesized using copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition with aryl or alkyl azides.
• Enzyme inhibition assays were performed to determine IC50 values against hPIP5K1α.
• Antiproliferative activity was assessed in LNCaP, PC3, and DU145 prostate cancer cell lines.

Main Results:

• Five compounds (3a, 3e, 3f, 3i, 3r) exhibited strong inhibition of hPIP5K1α with IC50 values ranging from 0.46 to 3.65 µM.
• Compound 3e was the most potent inhibitor, with an IC50 of 0.46 µM.
• Compound 3r demonstrated significant inhibition of prostate cancer cell proliferation at 20 µM and exhibited cytotoxic effects.

Conclusions:

• Novel totarol derivatives can effectively inhibit hPIP5K1α, a key enzyme in prostate cancer.
• The synthesized compounds show promise as potential therapeutic agents for prostate cancer, with compound 3r displaying significant antiproliferative and cytotoxic activity.