Synthesis, and the adjuvant and tumor-suppressive activities of quinonyl muramyl dipeptides.
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概要
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ω-(1,4-Benzoquinon-2-yl)alkanoic acids, 2-[10-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)decyl]-3-hydroxytetracosanoic acid, all-<I>trans</I>-5,9,13,17-tetramethyl-4,8,12,16-octadecatetraenoic acid, and stearic acid were coupled to the 6-<I>O</I>-position of the carbohydrate moiety of muramyl dipeptide alkyl esters, and 6-<I>O</I>-aminoacylmuramyl dipeptide methyl esters. The aminoacyl residues used were Gly, Leu, Ahx, and Aud. New synthetic methods were developed for ω-(1,4-benzoquinon-2-yl)alkanoic acids such as 22-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)docosanoic acid, and the α-branched ω-(1,4-benzoquinone-2-yl) β-hydroxy acid, 2-[10-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)decyl]-3-hydroxytetracosanoic acid. The effects of the resulting quinonyl, multiprenylacetyl, and stearoylmuramyl dipetides on the induction of delayed-type hypersensitivity to ABA-Tyr in guinea pigs and the tumor(meth-A)-suppressive activity in syngeneic BALB/c female mice were measured. The results revealed that all these muramyl-dipeptide derivatives retained the adjuvant activity whereas the potent tumor-suppressive activity was observed only in quinonylmuramyl dipeptides, indicating that the 5,6-dimethoxy-3-methyl-1,4-benzoquinone ring is a requisite for the manifestation of the tumor-suppressive activity. The lipophilicity-hydrophilicity balance of the molecule was also important. Among the compounds tested, <I>N</I>-acetyl-6-<I>O</I>-[10-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)decanoyl]muramyl-L-valyl-D-isoglutamine methyl ester showed the most potent tumor-suppressive activity. This compound also showed tumor-regressive activity in guinea pigs, and hence is a good candidate for further studies.
- 公益社団法人 日本化学会の論文
著者
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Fujino Masahiko
Central Research Division Takeda Chemical Ind. Ltd.
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Azuma Ichiro
Institute Of Immunological Cience
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YAMAMURA Yuichi
Osaka University
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Fukuda Tsunehiko
Central Research Division, Takeda Chemical Industries, Ltd.
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Kobayashi Shigeru
Central Research Division, Takeda Chemical Industries, Ltd.
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Yukimasa Hidefumi
Central Research Division, Takeda Chemical Industries, Ltd.
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