title: Synthesis and inhibitory effect of novel glycyrrhetinic acid derivatives on IL-1 beta-induced prostaglandin E(2) production in normal human dermal fibroblasts.
abstract: 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.
authors.affiliation: Research Laboratory, Minophagen Pharmaceutical Co., Ltd.; 2-2-3 Komatsubara, Zama, Kanagawa 228-0002, Japan. tsukhara@lab.minophagen.co.jp
authors.forename: Michiko
authors.initials: M
authors.lastname: Tsukahara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishino
authors.forename: Ikue
authors.initials: I
authors.lastname: Furuhashi
authors.forename: Hideo
authors.initials: H
authors.lastname: Inoue
authors.forename: Toshitsugu
authors.initials: T
authors.lastname: Sato
authors.forename: Hiroatsu
authors.initials: H
authors.lastname: Matsumoto
mesh_terms: D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D007202:Indicators and Reagents; D007375:Interleukin-1; D015232:Dinoprostone; D006034:Glycyrrhetinic Acid