Synthesis of 1,4-Thiazepane-Based Curcuminoids with Promising Anticancer Activity

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Pharmacology

Background:

• Curcumin, derived from turmeric, exhibits anticancer potential but suffers from low bioavailability and metabolic instability.
• Existing research focuses on modifying the planar curcumin structure to improve therapeutic efficacy.
• Novel structural modifications are needed to overcome curcumin's limitations.

Purpose of the Study:

• To synthesize and evaluate novel, out-of-plane 1,4-thiazepane-based curcuminoids.
• To assess the impact of this 3D structural modification on biological activity, including anticancer properties.
• To identify potential hit compounds with improved bioavailability and efficacy.

Main Methods:

• Synthesis of 21 new 1,4-thiazepane scaffolds (4-aryl-1-(7-aryl-1,4-thiazepan-5-ylidene)but-3-en-2-ones).
• Characterization of unexpected reaction products, including cyclohexenone derivatives.
• In vitro testing of synthesized analogues for antioxidant capacity, cytotoxicity, and reactive oxygen species (ROS) production.

Main Results:

• Ten novel curcuminoids, including eight 1,4-thiazepane derivatives, demonstrated superior antiproliferative properties compared to parent curcuminoids.
• Eight 1,4-thiazepane-based curcuminoids showed increased ROS production.
• Several synthesized compounds exhibited promising antioxidant and cytotoxic activities.

Conclusions:

• The novel 3D modification of the curcumin framework using a 1,4-thiazepane scaffold yields promising anticancer agents.
• These thiazepane-based curcuminoids offer improved antiproliferative activity and enhanced ROS generation.
• The developed compounds are suitable for further investigation as potential therapeutic agents.