Synthesis of Novel Aza‐aromatic Curcuminoids with Improved Biological Activities towards Various Cancer Cell Lines

• Published in: ChemistryOpen (Weinheim) Vol. 7; no. 5; pp. 381 - 392
• Main Authors: Theppawong, Atiruj, Van de Walle, Tim, Grootaert, Charlotte, Bultinck, Margot, Desmet, Tom, Van Camp, John, D'hooghe, Matthias
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.05.2018; John Wiley and Sons Inc
• Subjects: Anticancer properties; Antioxidants; Bioavailability; Biological activity; Biological effects; Cluster analysis; Clustering; cytotoxicity; Derivatives; enaminones; Nitrogen; nitrogen heterocycles; oxidative stress; Principal components analysis; Proteins; Solubility; Synthesis; biological activity; cytotoxicity; enaminones; oxidative stress; nitrogen heterocycles
• ISSN: 2191-1363; 2191-1363
• DOI: 10.1002/open.201800029

Curcumin, a natural compound extracted from the rhizomes of Curcuma longa, displays pronounced anticancer properties but lacks good bioavailability and stability. In a previous study, we initiated structure modification of the curcumin scaffold by imination of the labile β‐diketone moiety to produce novel β‐enaminone derivatives. These compounds showed promising properties for elaborate follow‐up studies. In this work, we focused on another class of nitrogen‐containing curcuminoids with a similar objective: to address the bioavailability and stability issues and to improve the biological activity of curcumin. This paper thus reports on the synthesis of new pyridine‐, indole‐, and pyrrole‐based curcumin analogues (aza‐aromatic curcuminoids) and discusses their water solubility, antioxidant activity, and antiproliferative properties. In addition, multivariate statistics, including hierarchical clustering analysis and principal component analysis, were performed on a broad set of nitrogen‐containing curcuminoids. Compared to their respective mother structures, that is, curcumin and bisdemethoxycurcumin, all compounds, and especially the pyridin‐3‐yl β‐enaminone analogues, showed better water solubility profiles. Interestingly, the pyridine‐, indole‐, and pyrrole‐based curcumin derivatives demonstrated improved biological effects in terms of mitochondrial activity impairment and protein content, in addition to comparable or decreased antioxidant properties. Overall, the biologically active N‐alkyl β‐enaminone aza‐aromatic curcuminoids were shown to offer a desirable balance between good solubility and significant bioactivity. Spice it up! Pyridine‐, indole‐, and pyrrole‐based curcumin analogues (aza‐aromatic curcuminoids) are prepared and their water solubility, antioxidant activity, and antiproliferative properties are discussed. All compounds show better water solubility profiles than curcumin and bisdemethoxycurcumin. Overall, these biologically active aza‐aromatic curcuminoids offer an appropriate balance between good solubility and significant bioactivity.