Antiallergic Activity of 3- O-Dodecyl-l-ascorbic Acid

Abstract

2-O-Alkyl-l-ascorbic acids and 3-O-alkyl-l-ascorbic acids were synthesized, and their degranulation inhibitory activities were evaluated. Among ascorbic acid derivatives with butyl, octyl, dodecyl, hexadecyl, and octadecyl groups introduced at the C-2 or C-3 positions, an AA derivative with a dodecyl group introduced at the C-3 position, 3-O-dodecyl-l-ascorbic acid (compound 8), showed the strongest inhibitory activity against antigen-stimulated degranulation. Compound 8 also inhibited calcium ionophore-stimulated degranulation. Compound 11, in which the hydroxyl group at the C-6 position of compound 8 was substituted with an amino group, and compound 12, in which the dodecyloxy group at the C-3 position of compound 8 was exchanged with a dodecylamino group, were synthesized, and these derivatives showed weaker inhibitory activity against antigen-stimulated degranulation than that of compound 8. In addition, orally administered compound 8 inhibited passive cutaneous anaphylaxis reactions in mice with a potency equal to that of oxatomide, an antiallergic agent. These results suggest that compound 8 may be a candidate for antiallergic treatment.

Keywords: RBL-2H3 cells; ascorbic acid derivatives; degranulation inhibitory activity; passive cutaneous anaphylaxis (PCA) reaction.

Figure 1

Chemical structures of 2-O-alkylascorbic acids (2-O-AlkylAA) and 3-O-alkylascorbic acids (3-O-AlkylAA).

Figure 2

Inhibitory activities of 2-O-AlkylAA (a) and 3-O-AlkylAA (b) against antigen-stimulated degranulation in RBL-2H3 cells. Oxatomide (75 μM) was used as a positive control. Anti-dinitrophenyl (DNP)-immunoglobulin E-sensitized RBL-2H3 cells were incubated with the indicated AA derivatives and stimulated with DNP-human serum albumin. All data represent means ± SD of three independent experiments. * p < 0.05 and ** p < 0.01 (Dunnett’s test) as compared with the control. ## p < 0.01 (t-test).

Figure 3

Inhibitory activities of compounds 4, 5, 8, and 9 against calcium ionophore A23187-stimulated degranulation in RBL-2H3 cells. Oxatomide (75 μM) was used as a positive control. All data represent means ± SD of three independent experiments. * p < 0.05 and ** p < 0.01 (Dunnett’s test) compared with the control.

Figure 4

Chemical structures of derivatives of compound 8 (compounds 11 and 12).

Figure 5

Inhibitory activities of compounds 11 (a) and 12 (b) against antigen-stimulated degranulation in RBL-2H3 cells. Oxatomide (75 μM) was used as a positive control. Anti-dinitrophenyl (DNP)-immunoglobulin E-sensitized RBL-2H3 cells were incubated with the indicated AA derivatives and stimulated with DNP-human serum albumin. All data represent means ± SD of three independent experiments. ** p < 0.01 (Dunnett’s test) as compared with the control. # p < 0.05 (t-test).

Figure 6

Inhibitory activity of compound 8 against the antigen-stimulated PCA reaction in mice. Mice were orally administered the indicated samples: control (n = 6), oxatomide at a dose of 100 μmol/kg b.w. (n = 5), and compound 8 at doses of 100 μmol/kg b.w. (n = 5) and 200 μmol/kg b.w. (n = 6). All data represent the means ± SE. * p < 0.05, ** p < 0.01 (Dunnett’s test) compared with the control.