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

Abstract

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.

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

“…Interestingly, compounds 3 c , e , h , l and 4 c even displayed comparable activity to the commercial doxorubicin drug. Previous work demonstrated that the introduction of azaheteroaromatic moieties leads to higher antiproliferative properties . Therefore, with the intention to combine antioxidant and antiproliferative properties, compounds 3–4 were designed in this work, and these compounds indeed showed an improved antiproliferative capacity, in addition to a better water solubility.…”

“…The synthetic procedure for the preparation of non‐symmetrical curcuminoids is based on previously reported optimized conditions for the synthesis of curcumin and symmetrical curcumin analogues ,. In this work, however, two consecutive condensation reactions with different aldehydes had to be executed in order to obtain the desired non‐symmetrical curcuminoids.…”

“…After we successfully obtained the desired products, we further investigated the physicochemical properties of these non‐symmetrical curcuminoids. In that respect, water solubility tests were performed on all newly synthesized compounds following a similar procedure as in a previous research ,. An excess amount of solid was dissolved in 0.1 M phosphate buffer (pH 6.8) using the shake flask method .…”

“…The reason behind the applied structure modifications was to retain antioxidant/antiproliferative properties. All newly synthesized derivatives were assessed for their antioxidant effects using the ferric reducing antioxidant power (FRAP) assay ,. The FRAP assay is generally used to evaluate chemical antioxidant activity, which is expressed as either Trolox equivalents or curcumin equivalents.…”

“…To address the previously mentioned shortcomings, our former research focused on the synthesis of structurally modified nitrogen‐containing curcumin analogues, such as β‐enaminone and symmetrical azaheteroaromatic curcuminoids, in order to improve their bioavailability ,. Interestingly, many analogues exhibited good cytotoxicity profiles (low IC 50 values) as compared to curcumin.…”