Progress towards water-soluble triazole-based selective MMP-2 inhibitors

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Pharmacology

Background:

• Improving water solubility is crucial for developing effective drug-like compounds.
• Matrix metalloproteinases (MMPs), particularly MMP-2, are implicated in cancer progression and metastasis.
• Previous research identified triazole-substituted hydroxamates as potential MMP-2 inhibitors.

Purpose of the Study:

• To synthesize novel α-sulfone, α-tetrahydropyran, and α-piperidine derivatives of clicked hydroxamates.
• To enhance the water solubility and inhibitory activity of MMP-2 inhibitors.
• To evaluate the anti-invasive and cytotoxic effects of these compounds on human fibrosarcoma cells.

Main Methods:

• Synthesis of new series of clicked hydroxamates.
• In vitro enzymatic assays to determine inhibitory activity against MMP-2 and MMP-9.
• In vitro permeability studies using Caco-2 cell monolayers.
• Molecular docking and molecular dynamics (MD) simulations.
• Assessment of cytotoxicity and anti-invasive activity on HT1080 cells.

Main Results:

• Compound 13e demonstrated low nanomolar activity against MMP-2 and was 26-fold less active against MMP-9.
• 13e exhibited a favorable selectivity profile against a panel of ten MMPs, including MMP-1, -8, and -14.
• At 10 μM, compounds reduced invasiveness of HT1080 cells by up to 80%.

Conclusions:

• The synthesized hydroxamate derivatives, particularly 13e, represent promising candidates for further preclinical development as MMP-2 inhibitors.
• The improved water solubility and potent inhibitory activity of 13e support its potential therapeutic application.
• These findings highlight the potential of targeting MMP-2 for cancer therapy, specifically in reducing tumor cell invasiveness.