Azobenzene-containing photoswitchable proteasome inhibitors with selective activity and cellular toxicity

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Drug Discovery

Background:

• Proteasome inhibitors are crucial in cancer therapy.
• Azobenzene-containing compounds offer tunable properties.
• Developing novel proteasome inhibitors with improved selectivity is essential.

Purpose of the Study:

• To synthesize and evaluate azobenzene-containing peptidic boronate esters.
• To assess the activity of different isomeric states (trans-enriched TAS and cis-enriched PSS) against proteasome subunits.
• To investigate the anti-cancer potential and selectivity of promising compounds.

Main Methods:

• Synthesis of azobenzene-based peptidic boronate esters.
• Evaluation of proteasome inhibitory activity against β5 and β1 subunits.
• Assessment of tumor cell growth inhibition and cytotoxicity in normal cells.

Main Results:

• Compounds 4c and 5a exhibited significant differences in activity between TAS and PSS.
• The trans-enriched TAS of 4c and 5a showed proteasome inhibition comparable to bortezomib and delanzomib.
• Cis-enriched 4c inhibited breast and colorectal carcinoma cell growth, with no observed cytotoxicity in non-malignant MCF-10A cells.

Conclusions:

• Azobenzene-containing peptidic boronate esters represent a promising class of proteasome inhibitors.
• Isomer-specific activity allows for targeted therapeutic strategies.
• Compound 4c demonstrates potential as a selective anti-cancer agent.