Hemithioindigo-based histone deacetylase inhibitors induce a light-dependent anticancer effect

Area of Science:

• Medicinal Chemistry
• Molecular Oncology
• Photopharmacology

Background:

• Photoswitchable molecules offer precise control over drug activity, addressing limitations of traditional therapies.
• Histone deacetylase inhibitors (HDACis) are promising oncology drugs but often lack selectivity.
• Localizing drug effects in tumors can improve therapeutic outcomes and reduce side effects.

Purpose of the Study:

• To design and synthesize novel photoswitchable histone deacetylase inhibitors (HDACis).
• To develop HDACis with light-dependent activity for targeted cancer therapy.
• To optimize the efficacy and selectivity of photoswitchable HDACis.

Main Methods:

• Synthesis of photoswitchable HDACis utilizing a hemithioindigo scaffold.
• Characterization of isomerisation conditions, thermal stability, and enzyme activity.
• Evaluation of cellular effects, including cancer cell viability, under different light conditions.

Main Results:

• Successful synthesis of photoswitchable HDACis based on the hemithioindigo scaffold.
• Optimized derivatives demonstrated up to 6-fold increased activity under illumination compared to darkness.
• The most potent derivative selectively reduced HeLa cell viability only when exposed to light.

Conclusions:

• A series of photoswitchable HDACis with a hemithioindigo moiety were developed.
• These compounds exhibit light-dependent control over both HDAC inhibition and cancer cell viability.
• This study presents a promising strategy for developing targeted photopharmacological anticancer agents.