29 生薬・合歓皮のJulibroside類の構造と天然配糖体の糖鎖を利用した新規配糖体の合成(口頭発表の部)

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1. Structures of Julibrosides in Albiziae Cortex and Their Cytotoxicity. The dried stem bark of Albizia julibrissin DURAZZ, Albiziae Cortex, is used as tonic in China and Japan. Since it had been found that the saponin fraction from this crude drug showed a cytotoxic activity against KB cell (IC_<50> 12.8μg/ml) by the general screening, we had investigated the genuine saponins in this crude drugs to reveal the following results: a. Three new triterpenoidal saponins named Julibroside I-III were isolated and their structures were determined based on spectral and chemical evidence. After alkaline hydrolysis, the prosapogenins were also prepared and tested for cytotoxicity. b. The structure-activity relationships for KB cell cytotoxicity of Julibrosides and prosapogenins suggested that both an α-L-arabinofuranosyl-(1→4)-[β-D-glucopyranosyl-(1→3)]-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosyl (a mimosatetraosyl) ester unit and a monoterpene-quinovopyranosyl moiety are crucial substituents for cytotoxicity. The hydroxy group at C-16 of aglycone may play an important role in mediating cytotoxicity and the N-acetylglucosamine moiety at C-3 seems to enhance activity because Julibroside III showed the strongest cytotoxicity. 2. Synthesis of Neosaponins by Chemical Trans-Glycosylation. From the above evidence (1.b.), the mimosatetraosyl moiety is essential to show cytotoxicity. While, during the course of studies on the leguminase plants, we found that the β-fabatriosyl [α-L-rhamnopyranosyl (1→2)-β-D-galactopyranosyl-(1→2)-β-D-glucuronopyranosyl] triterpene glycosides (oleanane glucuronides) are effective for experimental liver injuries. Since the oligosaccharide parts of natural glycosides seemed to play an important role for cytotoxic and hepatoprotective activities, we had planed to synthesis neosaponins by chemical transglycosylation and examined biological activities. a. The ester glycosidic bond (mimosatetraosyl moiety) could be selectively cleaved with lithium iodide in the presence of lutidine and allyl alcohol to give an allylglycoside. The allyl tetrasaccharide was converted to a ceramide like double-tailed glycolipid, following ozonolysis, reductive amination, and N-acylation. Futhermore the tetrasaccharide is converted to an α-trichloroimidate and glycosylated to diosgenin and glycyrrhitinic acid, respectively. Following deprotectin, a diosgenin and a glycyrrhitinic acid tetraglycosides were obtained. b. Glycyrrhizine hydrolase (GHase) selectively cleaves an ether linked end glucuronic acid at C-3 position of triterpene. The β-fabatriosyl moiety obtained by GHase from Soyasaponin I was glycosylated to diosgenin by the method as described above. c. The obtained neosaponins (1〜5) were tested for cytotoxicity against PC-6 and P388 cell lines. Although they were less active than CDDP and dioscin, compounds 2, 3, 4 showed some cytotoxicity. In spite of having the same tetrasaccharide(1〜4), the potency was different due to difference of aglycone part. The compounds 3, 4, 5 were tested for hepatoprotective activity using in vitro immunological liver injury model. Since the compound 5 showed an activity, the β-fabatriosyl moiety is appeared to be important for the hepatoprotective effect.
天然有機化合物討論会の論文
1997-07-20

29 生薬・合歓皮のJulibroside類の構造と天然配糖体の糖鎖を利用した新規配糖体の合成(口頭発表の部)

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