Synthesis and inhibitory effect of novel glycyrrhetinic acid derivatives on IL-1 beta-induced prostaglandin E(2) production in normal human dermal fibroblasts

• Published in: Chemical & pharmaceutical bulletin Vol. 53; no. 9; pp. 1103 - 1110
• Main Authors: Tsukahara, Michiko, Nishino, Takeshi, Furuhashi, Ikue, Inoue, Hideo, Sato, Toshitsugu, Matsumoto, Hiroatsu
• Format: Journal Article
• Language: English
• Published: Japan 01.09.2005
• Subjects: Cells, Cultured; Dinoprostone - biosynthesis; Fibroblasts - drug effects; Fibroblasts - metabolism; Glycyrrhetinic Acid - analogs & derivatives; Glycyrrhetinic Acid - chemical synthesis; Glycyrrhetinic Acid - pharmacology; Humans; Indicators and Reagents; Interleukin-1 - antagonists & inhibitors; Interleukin-1 - pharmacology; Magnetic Resonance Spectroscopy; Skin - cytology; Skin - drug effects; Skin - metabolism
• ISSN: 0009-2363

Olean-11,13(18)-dien-3beta,30-diol dihemiphthalate (3), which was derived from glycyrrhetinic acid (GA), has been reported to produce a potent of anti-inflammatory effect in in vivo assays. Using 3 as a lead compound, we attempted to synthesize some modified compounds which varied in the following; i) the position of a carboxyl group in the phthalate moiety, ii) the number of carboxyls attached to the benzoyl group, iii) conversion of benzene ring to another ring system, iv) the linkage form between the benzene ring and oleanene skeleton at position 3 and/or 30. These were screened for their inhibitory activity against interleukin-1 beta (IL-1 beta)-induced prostaglandin E(2) (PGE(2)) production in normal human dermal fibroblasts (NHDF). Although conversion of the ortho-carboxyl group of 3 into the meta-position or the para-position led to an increase in inhibitory activity, the elimination or increase of the carboxyl group resulted in loss of the inhibitory activity. Conversion of the ester bond to the amide bond at position 3 and/or 30 of 3 did not contribute to a significant increase in inhibitory activity. On the other hand, among the derivatives possessing an anthranilic acid moiety at position 30 of 3beta-O-acetyl-olean-11,13(18)-dien-30-oic acid (20), 3beta-hydroxy-30-nor-olean-11,13(18)-dien-20 beta-[N-(2-carboxyphenyl)]carboxamide (30) showed the most potent inhibitory activity (IC(50) 1.0 microM) in this series.