著者

浜道 則光 藤多 哲朗 松崎 徹 北尾 有紀 城内 正寿 広瀬 良治

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集 37 (ISSN:24331856)

巻号頁・発行日

pp.79-84, 1995-09-01 (Released:2017-08-18)

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Mycestericins D (1), E (3), F (2) and G (4), new immunosuppressants, were isolated from the culture broth of Mycelia sterilia ATCC 20349. The immunosuppressive activities of 1 and 2 exhibited an IC_<50> of 16nM and 120nM against mouse allogeneic mixed lymphocyte reaction (MLR), respectively, while 3 and 4 exhibited an IC_<50> of 13nM and 370nM, respectively. The proposed structures were unambiguously confirmed by spectroscopy, chemical evidence and total synthesis. Their absolute configurations have been determined by comparison of their CD spectra with those of synthetic compounds (R and S)-9 prepared from methyl (2S, 4R)-2-tert-butyl-3-formyl-oxazolidine-4-carboxylate (5) and stearoyl chloride. Thus, mycestericins D (1) and F (2) were assigned to be 2 (S), 3 (S) configurations, while mycestericins E (3) and G (4) were 2 (S), 3 (R) configurations. The first total synthesis of mycestericins have been achieved from 5 and 1,8-octanediole (10). The alkyl chain moiety 21 was prepared in 12 steps from 10 by straightforward reactioin. The key intermediate 22 obtained from 5 and 21 could be converted to the desired final compounds. Stereoselective reduction of the ketone 22 with Zn(BH_4)_2 or NaBH_4 provided the (R)-hydroxy 23, the protecting groups of which were removed with 10% MeOH in CF_3COOH, followed by hydrolysis of 24 to give mycestericin E (3). On the other hand, mycestericin D (1) was synthesized from 22 by deprotection, followed by reduction of 25 with Me_4NBH(OAc)_3 and then hydrolysis of 26. Hydrogenation of mycestericin D (1) and E (3) provided the corresponding F (2) and G (4).

著者

藤多 哲朗 浜道 則光 内田 秀治 加治 隆史 松本 範正 広瀬 良治 北尾 郁紀 松崎 徹 千葉 健治

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集 38 (ISSN:24331856)

巻号頁・発行日

pp.727-732, 1996-09-02 (Released:2017-08-18)

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2-Aminoalcohol was shown to be the minimum essential structure for the immunosuppressive activity of 2-alkyl-2-aminopropane-1,3-diol, which was generated by modification of ISP-I (1: myriocin, thermozymocidin). 2-Aminoalcohols 4a-h were examined for immunosuppressive activity on mouse allogeneic mixed lymphocyte reaction (MLR) in vitro. The series showed a bell-shaped relationship between the activity and the carbon numbers. Among them, 2-aminohexadecanol (4c) was the most potent. In order to investigate relationship between the activity and the configuration at C-2 in 2-aminoalcohol, (R)- and (S)-isomers of 4c, 2-aminoeicosanol (4h) and 2-amino-4-(4-octylphenyl)butanol (5) were prepared and examined for the activity on mouse allogeneic MLR. As a results, the (R)-isomers were more potent the (S)-isomers, and (R)-4c displayed comparably activity to FTY720 (3), which is expected as a powerful candidate for safer immunosuppressant for organ transplantations and for the treatment of autoimmune diseases.