Synthesis of Non‐Symmetrical Nitrogen‐Containing Curcuminoids in the Pursuit of New Anticancer Candidates

Abstract

Curcumin is known to display pronounced anticancer effects and a variety of other biological activities. However, the low bioavailability and fast metabolism of this molecule present an issue of concern with respect to its medicinal applications. To address this issue, structural modifications of the curcumin scaffold can be envisioned as a strategy to improve both the solubility and stability of this chemical entity, without compromising its biological activities. Previous work in our group targeted the synthesis of symmetrical azaheteroaromatic curcuminoids, which showed better solubility and cytotoxicity profiles compared to curcumin. In continuation of that work, we now focused on the synthesis of non‐symmetrical nitrogen‐containing curcuminoids bearing both a phenolic and an azaheteroaromatic moiety. In that way, we aimed to combine good solubility, antioxidant potential and cytotoxic properties into one molecule. Some derivatives were selected for further chemical modification of their rather labile β‐diketone scaffold to the corresponding pyrazole moiety. In this way, thirteen new non‐symmetrical aza‐aromatic curcuminoids and four pyrazole‐based analogues were successfully synthesized in a yield of 11–69 %. All newly synthesized analogues were evaluated for their antioxidant properties, reactive oxygen species (ROS) production, water solubility and anticancer activities. Several novel derivatives displayed good cytotoxicity profiles compared to curcumin, in combination with an improved water solubility and stability, and were thus identified as potential hit scaffolds for further optimization studies.

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

“…The synthetic yields of aldol condensation reactions between benzaldehyde analogues and pentane-2,4-dione to generate curcuminoids (1-10) are dependent on several factors including solvent, catalyst, reaction time, complexing agent, water scavenger and temperature [5,6,9,21,22,31] (see the Supporting Information for the synthetic procedure). The ratio of aldehyde and pentane-2,4-dione (2 : 1) would minimize side reactions due to the consumption of reactants.…”

“…[37] The apoptotic activity of curcumin on tumor cells correlated closely with the formation of ROS. [6,38,39] Curcumin can generate a reactive free radical by abstracting an H-atom from the phenolic group. The high antioxidant capacity may be due to the stabilization of phenoxyl radical, in which a double bond in conjugation with the phenyl ring is present.…”

“…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.…”

“…Among them, a series of heterocycles such as pyrazole rings resulted from a cyclization between 1,3-diketone group and hydrazine has attracted tremendous attention due to their promising biomedical applications. Replacing the β-diketone by pyrazole ring may increase anticancer activities, [6,[13][14][15][16][17] water solubility and delay degradation of curcumin. [6,15,16,[18][19][20] In order to prepare pyrazole-modified analogues of curcumin, the amount of curcumin substrate needs to be large enough for semi-synthetic processes.…”

“…The invention of a process for the synthesis of curcumin-related compounds was reported. [6,9,21,22] In present work, we present a synthetic procedure of pyrazole curcuminoids through two steps, in which, at first, benzaldehyde analogues undergo aldol condensation reactions with pentane-2,4-dione. The 1,3-diketone group of resulting curcuminoids is then cyclized to generate pyrazole curcuminoids ( Figure 1).…”