Structure–activity analysis of 2′-modified cinnamaldehyde analogues as potential anticancer agents

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Abstract

The natural product 2′-hydroxycinnamaldehyde (HCA) and its analogue, 2′-benzoyloxycinnamaldehyde (BCA), have been previously shown to have antiproliferative and proapoptotic effects in vitro and inhibit tumor growth in vivo. In this study, we use structure–activity analysis to define structural features that are important for the activity of cinnamaldehyde analogues. Our results emphasize an important role for both the propenal group as well as the modification at the 2′-position. Further studies were aimed to characterize the mechanism of action of BCA. Exposure to BCA induced cell death via caspase-dependent and -independent pathways. Cell death was not due to autophagy or necrosis as a result of energy depletion or induction of reactive oxygen species. Our findings have important implications for future drug design and highlight the importance of defining molecular drug targets for this promising class of potential anticancer agents.

Introduction

2′-Hydroxycinnamaldehyde (HCA), which is derived from the stem bark of Cinnamomum cassia, and the analogue 2′-benzoyloxycinnamaldehyde (BCA) have been shown to induce growth arrest and apoptosis in tumor cells [1]. BCA, administered intraperitoneally or orally, has also been demonstrated to inhibit tumor growth of xenografts in nude mice [1], thus making cinnamaldehyde analogues promising therapeutic agents for further development.

A number of mechanisms of action for HCA and BCA have been proposed. It has been reported that HCA and BCA induce apoptosis in cancer cells via the induction of cellular reactive oxygen species (ROS) [1]. HCA has also been reported to inhibit farnesyl protein transferase activity in vitro[2] as well as to inhibit AP-1 and NF-κB transcriptional activity in colon cancer cells [3], [4]. Activation of the ERK pathway was suggested to be involved in HCA-dependent inhibition of NF-κB and cell growth [3]. Furthermore, HCA has been shown to inhibit the 26S proteasome and induce an endoplasmic reticulum stress response [5] as well as to downregulate the antiapoptotic protein Bcl-2 [3], [4].

In this study, we aimed to elucidate the structural requirements for the antitumor activity of cinnamaldehyde analogues, specifically focusing on the importance of the propenal group and modification at the 2′-position. The propenal constitutes a Michael acceptor which may be important for the activity of cinnamaldehyde analogues. In addition, we sought to improve our understanding of the mechanism of action of BCA. Our results highlight the importance of both the modification in the 2′-position and the propenal group. Furthermore, BCA was found to induce cell death via caspase-dependent as well as caspase-independent pathways.

Section snippets

Materials and methods

Chemical synthesis. 2-Methoxycinnamaldehyde (SSP1) was commercially available (Sigma–Aldrich). Following esterification of commercially available (E)-2-hydroxycinnamic acid, the phenol group was protected using the appropriate alkyl halide to give the methyl (2-alkoxy)-cinnamate product. Ester reduction using Red-Al gave access to compounds BCA, SSP2, SSP3 and SSP4. Removal of the p-methoxybenzyl group of SSP4 using ceric ammonium nitrate (CAN) gave rise to 2-hydroxycinnamaldehyde (HCA) (see

Effects of cinnamaldehyde analogues on cell viability and apoptosis

HCA and BCA have previously been shown to inhibit cell proliferation and induce apoptosis in cancer cells. To determine the importance of the aldehyde group and the functional group in the 2′-position, we evaluated the effect of trans-cinnamic acid, trans-cinnamaldehyde (which lacks a modification at the 2′-position), HCA, BCA, and a number of novel compounds with different modifications in the 2′-position (see Fig. 1C) that were synthesized as described under Materials and methods. When

Discussion

HCA and BCA have previously been shown to have anti-cancer activity in vitro and in vivo and are considered as promising drug candidates for further development [1]. The goal of this study was to gain further insights into the structural requirements for the anti-cancer activity of cinnamaldehyde analogues as well as to obtain a better understanding of their mechanism of action. Our structure–activity analysis revealed an important role for both the propenal group as well as the functional

Acknowledgments

We thank Charles Matthews and Chia Yee Tan for preparing Bcl-xL overexpressing cells and Dr. David Beach (Institute of Cell and Molecular Science, London) for providing the lentiviral expression vector Puro-MaRX. This work was supported by a grant from the Singapore Academic Research Fund (AcRF Tier 1, FRC level).

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