Bioisoster of Caffeic Acid: Syntheses of 1-Hydroxy-2-pyridone Analogues (2008)

Caffeic acid is a naturally occurring phenolic compound that is found in many fruits, vegetables, and herbs (e.g. sage), including coffee. Caffeic acid and its analogues have attracted much attention and have been studied in recent years because of their antiviral, anti-inflammatory, and neuroprotective properties, and their antioxidant effects. In particular, their antioxidative effects can be used for either the prevention of oxidative rancidity in foods or the treatment of diseases related to reactive oxygen species, such as stroke and Alzheimer’s diseases. However, since caffeic acid is not approved for direct use in food, due to it being a suspected human carcinogen based on testing in mice, there is still a need to develop an analogue that has similar biological properties. Bioisosterism is considered to be a powerful method for selecting molecular groups for drug design and lead compound development. By the application of bioisosterism, we previously found that replacing the catechol moiety in dopamine with 1-hydroxy-2-pyridone analogues resulted in similar dopaminergic activity. Based on those results, we replaced the functional catechol moiety in caffeic acid with 1-hydroxy-2-pyridone systems whose isosteric and isoelectric character are considered to be equivalent. Therefore, they are interchangeable in terms of their contributions to biological activity. In this article, we describe the syntheses of two 1-hydroxy-2-pyridone analogues (compounds 1 and 2) of caffeic acid and the evaluation of their antioxidant activities by an in vitro 1,1diphenyl-2-picryl-hydrazyl free radical (DPPH·) scavenging assay. The synthesis of the 5-substituted 1-hydroxy-2-pyridone analogue (1) is illustrated in Scheme 1. The Horner-Wadsworth-Emmons reaction of 6-methoxynicotin aldehyde using triethyl phosphonoacetate, lithium hydroxide (LiOH), and 4 A molecular sieves in tetrahydrofuran (THF) at room temperature gave ethyl 3-(6-methoxypyridin-3-yl)acrylate (3) in 82% yield. N-Oxidation of compound 3 with mchloroperbenzoic acid (m-CPBA) gave the N-oxide compound 4 in 68% yield. Removal of the methyl group with acetyl chloride under reflux conditions, followed by hydrolysis with an acetone-water mixture gave compound 5. Finally, base-catalyzed hydrolysis of the ester group in 5 gave the desired 5-substituted 1-hydroxy-2-pyridone analogue (1). As shown in Scheme 2, the synthesis of the 4-substituted 1-hydroxy-2-pyridone analogue (2) is started from methyl 2chloroisonicotinate, due to the commercial unavailability of 2-methoxynicotinaldehyde (8). For the synthesis of 8, methyl 2-chloroisonicotinate was first reacted with sodium methoxide in 1,4-dioxane to give a mixture of compound 6 and 2-chloroisonicotinic acid. The mixture resulted because de-esterification also occurred in the presence of the sodium methoxide. Reduction of the ester compound 6 with sodium borohydride and calcium chloride in THF gave compound 7, which was then partially oxidized with chromium (VI) oxide in dichloromethane to give compound 8. From the aldehyde compound 8, the target compound 2 was synthesized by the same reactions as those described for the synthesis of compound 1 from 6-methoxynicotinaldehyde (depicted in Scheme 1). The antioxidant activities of the synthesized 1-hydroxy-2pyridone analogues and caffeic acid were measured using the previously reported DPPH method, and the results are shown in Table 1. Although caffeic acid showed potent radical scavenging activity, the 1-hydroxy-2-pyridone analogues did not show any activity. These results clearly indicate that the antioxidant activity of caffeic acid is mainly attributed to the catechol moiety. In conclusion, two 1-hydroxy-2-pyridone analogues of Figure 1. Structure of caffeic acid.