Takeo Mori

Modulation by glycyrrhetinic acid derivatives of TPA-induced mouse ear oedema.

1 The anti‐inflammatory effects of glycyrrhetinic acid and its derivatives on TPA (12‐0‐tetradecanoylphorbol‐13‐acetate)‐induced mouse ear oedema were studied. The mechanisms of TPA‐induced ear oedema were first investigated with respect to the chemical mediators. 2 The formation of ear oedema reached a maximum 5 h after TPA application (2 μg per ear) and the prostaglandin E2 (PGE2) production of mouse ear increased with the oedema formation. 3 TPA‐induced ear oedema was prevented by actinomycin D and cycloheximide (0.1 mg per ear, respectively) when applied during 60 min after TPA treatment. 4 Of glycyrrhetinic acid derivatives examined, dihemiphthalate derivatives (IIe, IIe′, IIIa, IIIa′, IVa, IVa′) most strongly inhibited ear oedema on both topical (ID50, 1.6 mg per ear for IIe, 2.0 mg per ear for IIIa and 1.6 mg per ear for IVa) and oral (ID50, 88 mg kg−1 for IIe′, 130 mg kg−1 for IIIa′ and 92 mg kg−1 for IVa′) administration. 5 Glycyrrhetinic acid (Ia) and its derivatives applied 30 min before TPA treatment were much more effective in inhibiting oedema than when applied 30 min after TPA. A dihemiphthalate of triterpenoid compound IVa completely inhibited oedema, even when applied 3 h before TPA treatment. 6 Glycyrrhetinic acid (Ia) and deoxoglycyrrhetol (IIa), the parent compounds, produced little inhibition by oral administration at less than 200 mg kg−1 7 These results suggest that the dihemiphthalate derivatives of triterpenes derived from glycyrrhetinic acid by chemical modification are useful for the treatment of skin inflammation by both topical and oral application.

Sulfidopeptide-leukotrienes are major mediators of arachinodic acid-induced mouse ear edema

The inflammatory response of the mouse ear to topical application of arachidonic acid (2 mg/ear) was examined to study the roles of sulfidopeptide-leukotrienes (LTs) and prostaglandin (PG) E2 as mediators of edema. The increase in ear thickness caused by arachidonic acid (AA) (edema), reached a maximum at 45 to 60 min after AA application. The amounts of immunoreactive LTC4 and immunoreactive PGE2 produced increased significantly in 5 to 10 min, and then diminished gradually over 60 min. 5-lipoxygenase inhibitors, dual cyclooxygenase/lipoxygenase inhibitors and anti-histamines significantly inhibited AA-induced ear edema. Both production of PGE2 and LTC4 were suppressed by NDGA at 1 mg/ear which also inhibited ear swelling. However aspirin, which enhanced LTC4 production in AA-induced ear edema did not inhibit the ear swelling. Hypodermic injection of LTC4 at 25 ng or PGE2 at 500 ng/ear did not cause swelling, but edema was induced when both compounds were injected simultaneously. Moreover ear swelling was induced by injection of both LTD4 at 50 ng and PGE2 at 500 ng/ear. Furthermore, concomitant injection of histamine, at 500 ng or serotonin at 50 ng/ear with LTC4 at 25 ng caused ear swelling but both compounds at the same dose alone did not induce swelling. These results suggest that AA-induced ear edema is predominantly mediated by LTC4 and other lipoxygenase products while PGE2 (in the presence of LTs) acts to facilitated ear swelling, although serotonin and histamine may also contribute.

Inhibitory Effect of Glycyrrhetinic Acid Derivatives on Arachidonic Acid‐induced Mouse Ear Oedema

Abstract— The inhibitory effects of glycyrrhetinic acid and its derivatives were examined on arachidonic acid (AA)‐induced ear oedema in mice. Of the compounds, dihemiphthalate derivatives of 18β‐olean‐12‐ene‐3β, 30‐diol (IId, IId′), 18β‐olean‐9(11)12‐diene‐3β, 30‐diol (IIIa, IIIa′) and olean‐11,13(18)‐diene‐3β, 30‐diol (IVa, IVa′) showed a strong inhibition of ear oedema on both topical (ID50, 1.9, 2.8 and 1.7 mg/ear, respectively) and oral (ID50, 90, 130 and 88 mg kg−1, respectively) administration. Topical ID50 values were approximately the same potency as nordihydroguaiaretic acid (ID50, 2.1 mg/ear). Given topically these compounds were also capable of inhibiting PGE2 and LTC4 formation at an early stage of AA‐induced ear oedema. However, glycyrrhetinic acid (Ia) and deoxoglycyrrhetol (IIa), the fundamental skeletons of the derivatives, showed no detectable inhibition of oedema at a dose of 1 mg/ear (topical) or 200 mg kg−1 (oral). The most effective time for the topical administration of the compound IId against ear oedema was 0–30 min before AA application; this is different from dexamethasone which requires a time lag for reaction. The results suggest that the inhibitory effect of the hemiphthalate compounds (IId, IId′, IIIa, IIIa′, IVa and IVa′) is a direct action, and does not involve the anti‐inflammatory action of steroids mediated by the secondary formation of a reactive protein.

Glycyrrhetinic acid derivatives: anti-nociceptive activity of deoxoglycyrrhetol dihemiphthalate and the related compounds

Abstract— The possible inhibitory effect of deoxoglycyrrhetol dihemiphthalate (I) and the related compounds (18β‐olean‐9(11), 12‐diene‐3β,30‐diol) (II) and (olean‐11,13(18)‐diene‐3β,30‐diol) III derived from glycyrrhetinic acid has been examined on acetic acid‐induced writhing in mice. The compounds inhibited writhing dose‐dependently. Their ED50 values were 14,31 and 22 mg kg−1 for I, II, and III, respectively. The compounds like aspirin, also significantly suppressed PGE2 production in peritoneal fluid together with the writhing response. The results suggests that the analgesic effect of deoxoglycyrrhetol dihemiphthalate and the related compounds is partially due to inhibition of PGE2 production.

Synthesis of 6-Sulfur Analogues of Oxanosine and Closely Related Derivatives Thereof

Abstract Novel β-D-ribofuranosides having a 5-substituted imidazo [4,5-d] [1,3]thiazine ring, including the S6-congener 3 of oxanosine 2, were synthesized for screening their anticancer and antiviral activities.