Cancer Letters

Cancer Letters

Volume 153, Issues 1–2, 29 May 2000, Pages 51-56
Cancer Letters

Preferential cytotoxicity of caffeic acid phenethyl ester analogues on oral cancer cells

https://doi.org/10.1016/S0304-3835(00)00389-XGet rights and content

Abstract

As part of our previous search for new compounds with improved biological activities including antibiotic, antiviral, anti-inflammatory, and tumor growth inhibition activities, we synthesized some caffeic acid phenethyl ester (CAPE)-like compounds from commercially available caffeic acid. Nine chemicals were tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay on the growth of buccal mucosal fibroblast (BF), oral submucosus fibroblast (OSF), neck metastasis of Gingiva carcinoma (GNM), and tongue squamous cell carcinoma (TSCCa) cells. CAPE and its ethyl analogue show significant cytotoxicity on OSF, GNM, and TSCCa cells, but not on BF cells. The results suggest that CAPE-like compounds may be potential chemotherapy agents against oral cancer.

Introduction

Recently we synthesized [1] and studied [2] the constituents of natural honey-propolis, which is a folk medicine employed for treating various ailments. We assayed them in peripheral blood mononuclear cells (PBMC) infected by M-tropic (JRCSF), T-tropic (NL-4-3), and Dual tropic (89.6) of HIV-1 isolates. Caffeic acid phenethyl ester (CAPE) and caffeic acid methyl ester (MC) showed significant inhibition on the growth of HIV-replication in PBMC cells. 3-(3,4-Dimethoxy-phenyl)-acrylic phenethyl ester (PEDMC) showed less inhibition effect than CAPE or MC. CAPE-like analogues exhibited a broad spectrum of medical applications including antibiotic, antiviral, anti-inflammatory, and tumor growth inhibition [3], [4], [5]. Furthermore, Rao et al. have shown that CAPE has chemoprevention [6], [7], [8], [9], [10] and antitumor properties [11], [12]. Since the biological properties of propolis and its constituent compounds have become a point of particular interest, and extraction of these compounds required large quantities of propolis, we have designed and undertaken the synthesis of nine CAPE-like analogues for investigating oral cancer.

The commercial availability of caffeic acid prompted us to prepare some caffeic acid esters from this compound. However, selective esterification of the α, β-unsaturated carboxyl group presents a problem because of the solubility of caffeic acid. Although CAPE (1) has been synthesized by several groups [7], [13], [14], their preparations gave only poor yields of the target compound and the synthetic approaches are very time consuming and complicated. To overcome these technical difficulties, we have found that CAPE and its derivatives can be easily prepared in a one pot reaction in high yield (86%) [15].

We report herein the effect of nine agents on the growth of normal human buccal mucosal fibroblast (BF), oral submucosus fibroblast (OSF), neck metastasis of Gingiva carcinoma (GNM), tongue squamous cell carcinoma (TSCCa) cells using the MTT assay. Differential cytotoxicity was observed in BF versus GNM and TSCCa cell lines in the presence of nine synthetic CAPE-like analogues.

Section snippets

Chemicals

Phenethyl 3-(3,4-dihydroxyphenyl)acrylate (CAPE), phenethyl 3-(3,4-dimethoxyphenyl)acrylate (PEDMC), methyl 3-(3,4-dihydroxyphenyl)acrylate (MC), ethyl 3-(3,4-dihydroxyphenyl)acrylate (EC), phenethyl 3-(4-bromophenyl)acrylic (BrCAPE), ethyl 3-(3,4-dimethoxyphenyl)acrylate (6), ethyl 3-(4-methoxyphenyl)acrylate (7) were synthesized by our developed procedure. Ethyl 2,3-dibromo-3-(3,4-dimethoxyphenyl) propiolate (8) and ethyl 2,3-dibromo-3-(4-methoxyphenyl) propiolate (9) were prepared by a

Results and discussion

Our previous synthetic method was performed with nitrobenzene to provide CAPE in 50% yield. It was worth noting that although reactions described could be regarded, as straightforward, manipulations were sometimes difficult due to the synthesis and solubility of the acid chloride. In addition, there are health risks from toxic solvents, such as benzene and nitrobenzene. Furthermore the methods required substantial amounts of alcohol, reagents, and solvents for esterification. To overcome these

Acknowledgements

The authors are indebted to Dentist Yi-Chao Chang for the generous gift of BF, OSF, GNM and TSSCa cells. For financial support, we thank the National Science Council of the Republic of China (Research Grant NSC 87-2113-M-040-001).

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