| Summary: | Allergy is an excessive immune response to a specific antigen. Type I allergies, such as hay fever and food allergies, have increased significantly in recent years and have become a worldwide problem. We previously reported that an ascorbic acid derivative having palmitoyl and glucosyl groups, 2-<i>O</i>-α-<span style="font-variant: small-caps;">d</span>-glucopyranosyl-6-<i>O</i>-hexadecanoyl-<span style="font-variant: small-caps;">l</span>-ascorbic acid (6-sPalm-AA-2G), showed inhibitory effects on degranulation in vitro and on the passive cutaneous anaphylaxis (PCA) reaction in mice. In this study, several palmitoyl derivatives of ascorbic acid were synthesized and a structure–activity relationship study was performed to discover more potent ascorbic acid derivatives with degranulation inhibitory activity. 6-Deoxy-2-<i>O</i>-methyl-6-(<i>N</i>-hexadecanoyl)amino-<span style="font-variant: small-caps;">l</span>-ascorbic acid (2-Me-6-<i>N</i>-Palm-AA), in which a methyl group was introduced into the hydroxyl group at the C-2 position of ascorbic acid and in which the hydroxyl group at the C-6 position was substituted with an <i>N</i>-palmitoyl group, exhibited much higher inhibitory activity for degranulation in vitro than did 6-sPalm-AA-2G. 2-Me-6-<i>N</i>-Palm-AA strongly inhibit the PCA reaction in mice at lower doses than those of 6-sPalm-AA-2G. These findings suggest that 2-Me-6-<i>N</i>-Palm-AA may be a promising therapeutic candidate for allergic diseases.
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