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

Theppawong, Atiruj; Van de Walle, Tim; Van Hecke, Kristof; Grootaert, Charlotte; Van Camp, John; D'hooghe, Matthias

Curcumin, the main component of turmeric (Curcuma longa) is known to display an interesting bioactivity profile, including pronounced anticancer properties. However, its low bioavailability, metabolic instability and nonspecific activity are concerns that have to be addressed before curcuminoids can be considered for therapeutic applications. Within that framework, intensive research has been carried out in the last decades to develop new curcumin derivatives, generally centered on standard modifications of the sp2 curcumin framework, with the aim to augment its bioavailability while maintaining or improving its anticancer properties. To find potential hit molecules by moving away from the classical flat curcumin framework, we investigated an unexplored modification to produce novel, out‐of‐plane 1,4‐thiazepane‐based curcuminoids and assessed the impact of this modification on the biological activity. In this way, 21 new, structurally diverse thiazepane scaffolds (4‐aryl‐1‐(7‐aryl‐1,4‐thiazepan‐5‐ylidene)but‐3‐en‐2‐ones) were synthesized, as well as some biologically interesting unexpected reaction products (such as 5‐aryl‐6‐arylmethylene‐3‐ethoxycyclohex‐2‐en‐1‐ones and 4‐acetyl‐5‐aryl‐2‐(3‐arylacryloyl)‐3‐methylcyclohex‐2‐en‐1‐ones). All these analogues were subsequently tested on their antioxidant capacity, their cytotoxicity properties and their ROS (reactive oxygen species) production. Many compounds demonstrated interesting activities, with ten curcuminoids, whereof eight 1,4‐thiazepane‐based, showing better antiproliferative properties compared to their mother compounds, as well as an increased ROS production. This unprecedented 3D curcumin modification has thus delivered promising new hit compounds with good activity profiles eligible for further exploration.

CURCUMINOIDS; TURMERIC; ANTIOXIDANT testing; CURCUMIN; OXIDANT status; REACTIVE oxygen species

Chemistry - A European Journal, 2019, Vol 25, Issue 54, p12583

0947-6539

Academic Journal

10.1002/chem.201902549