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

Abstract

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 versus Pyrazole‐Modified Analogues: Synthesis and Cytotoxicity against HepG2 Cancer Cell Line

“…The fluorinated curcuminoids were synthesized to evaluate their inhibitory activities against HepG2 and compare with the activities of 1,3-diketone curcumin analogues. The presence of fluorine atom(s) in aromatic rings displayed close (7,9) or lower (8, 10) inhibitory activities respecting to compounds (1)(2)(3). As mentioned, the para-substituted À OH group is responsible for generating phenoxyl radical which is the crucial species for apoptosis.…”

“…Therefore, the lower activities of fluorinated curcuminoids could be observed. Note that compounds (7,9) bearing fluoro groups at meta-positions in aromatic rings remain cytotoxicity, suggesting the effect of fluoro meta-substitution on their inhibitory activities.…”

“…Experimental and computational studies on curcumin structure demonstrated that the aromatic ring/substituents on it and β-diketone moieties are crucial for biological responses and kinetic stability. [1][2][3][4][5][6][7][8][9][10][11][12] Several synthetic curcumin analogues have been developed through chemical modifications on its pharmacophores such as pyrazole, [6,[13][14][15][16][17][18][19][20] 1,4-thiazepane, [7] monocarbonyl, [8] aza-aromatic, [9] N-alkyl β-enaminone curcuminoids. [10][11][12] to circumvent the limitations of curcumin.…”

“…However, despite all its reported benefits, the clinical applications of curcumin have been limited due to its poor aqueous solubility and rapid degradation in the body. Experimental and computational studies on curcumin structure demonstrated that the aromatic ring/substituents on it and β ‐diketone moieties are crucial for biological responses and kinetic stability . Several synthetic curcumin analogues have been developed through chemical modifications on its pharmacophores such as pyrazole, 1,4‐thiazepane, monocarbonyl, aza‐aromatic, N ‐alkyl β ‐enaminone curcuminoids .…”

Synthesis and cytotoxicity of substituted aromatic curcuminoids against human oral epidermal carcinoma-KB cell line

“…Curcumin (1), a constituent of turmeric powder derived from the rhizome of C. longa, is an attractive compound with broad-spectrum capacities including anti-oxidant 5 , anti-inflammatory 6 , and antitumour 7 activities. In particular, many studies reported that curcumin exhibited anti-cancer activity in a wide range of human cancers [8][9][10][11][12][13][14][15] . In addition, curcumin is pharmacologically safe as large quantities of curcumin, up to 10 g per day, can be consumed without inflicting toxicity 16 .…”