著者

山田 靜之 木越 英夫

出版者

社団法人 有機合成化学協会

雑誌

有機合成化学協会誌 (ISSN:00379980)

巻号頁・発行日

vol.53, no.1, pp.13-21, 1995-01-01

参考文献数

22

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Synthetic studies on the bracken ultimate carcinogen (3) and its artificial analogues (32, 33) are described. The synthesis of (-) -ptaquilosin (2) the aglycon of a potent carcinogen ptaquiloside (1) from bracken and its (+) - enantiomer (<I>ent</I>- 2) was achieved starting with (+) -dimenthyl (1<I>R</I>, 2<I>R</I>) -cyclopentane-1, 2-dicarboxylate. Dehydration of ptaquilosin (2) under weakly basic conditions led to the ultimate carcinogen (3). DNA cleaving activities of both enantiomers (3) were compared, the one (3) derived from natural (-) -ptaquilosin (2) being more efficient. Reactivities of the ultimate carcinogen (3) toward DNA are described. DNA was shown to be alkylated at the particular sites of purine bases and to undergo cleavage. The molecular mechanism of DNA cleavage with the ultimate carcinogen (3) was disclosed using deoxytetranucleotide d (GTAC) as a model DNA substrate.

著者

武藤 毅 近藤 隆史 柴田 拓伸 曽根 大紀 藤田 達也 桐生 稔 木越 英夫 小鹿 一 山田 靜之

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

巻号頁・発行日

vol.37, pp.230-235, 1995

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Constituents of the Japanese sea hare Dolabella auricularia collected in Mie Prefecture, Japan were examined by using bioassay, and new cytotoxic depsipeptides, dolastatins G (1) and H (14) and isodolastatin H (15) were isolated. Dolastatin G (1) showed cytotoxicity against HeLa-S_3 cells with an IC_<50> of 1.0μg/mL. On the basis of 2D NMR technique, dolastatin G (1) has proved to be a 35-membered cyclic depsipeptide which consists of a hexapeptide and two new hydroxy acids. The absolute stereochemistry of the hexapeptide moiety was determined by the chiral HPLC analysis of amino acids obtained by acidic hydrolysis of dolastatin G (1). The absolute stereochemistry of two hydroxy acid parts was determined by the enantioselective synthesis of two corresponding fragments obtained by degradation of dolastatin G (1). For the purpose of confirming the stereostructure of dolastatin G (1), synthetic studies on dolastatin G (1) have been carried out. Three subunits, 7, 10, and 11, were synthesized, coupling of which gave seco acid 13. The synthesis of dolastatin G (1) from seco acid 13 is in progress. A 1:1 mixture of dolastatin H (14) and isodolastatin H (15) showed potent cytotoxicity against HeLa-S_3 cells with an IC_<50> of 0.00381μg/mL. On the basis of spectroscopic data, dolastatin H (14) has proved to be a linear tetrapeptide which contains two unusual amino acids and is esterified at the C-terminus by the primary hydroxyl group of 3-phenyl-1,2-propanediol. Isodolastatin H (15) is the structural isomer of dolasatin H (15), in which the tetrapeptide is esterified at the C-terminus by the secondary hydroxyl group of 3-phenyl-1,2-propanediol. The absolute stereochemistry of dolastatin H (14) and isodolastatin H (15) was unambiguously determined by the enantioselective total synthesis.

著者

武藤 毅 近藤 隆史 柴田 拓伸 曽根 大紀 藤田 達也 桐生 稔 木越 英夫 小鹿 一 山田 靜之

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

巻号頁・発行日

vol.37, pp.230-235, 1995

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Constituents of the Japanese sea hare Dolabella auricularia collected in Mie Prefecture, Japan were examined by using bioassay, and new cytotoxic depsipeptides, dolastatins G (1) and H (14) and isodolastatin H (15) were isolated. Dolastatin G (1) showed cytotoxicity against HeLa-S_3 cells with an IC_<50> of 1.0μg/mL. On the basis of 2D NMR technique, dolastatin G (1) has proved to be a 35-membered cyclic depsipeptide which consists of a hexapeptide and two new hydroxy acids. The absolute stereochemistry of the hexapeptide moiety was determined by the chiral HPLC analysis of amino acids obtained by acidic hydrolysis of dolastatin G (1). The absolute stereochemistry of two hydroxy acid parts was determined by the enantioselective synthesis of two corresponding fragments obtained by degradation of dolastatin G (1). For the purpose of confirming the stereostructure of dolastatin G (1), synthetic studies on dolastatin G (1) have been carried out. Three subunits, 7, 10, and 11, were synthesized, coupling of which gave seco acid 13. The synthesis of dolastatin G (1) from seco acid 13 is in progress. A 1:1 mixture of dolastatin H (14) and isodolastatin H (15) showed potent cytotoxicity against HeLa-S_3 cells with an IC_<50> of 0.00381μg/mL. On the basis of spectroscopic data, dolastatin H (14) has proved to be a linear tetrapeptide which contains two unusual amino acids and is esterified at the C-terminus by the primary hydroxyl group of 3-phenyl-1,2-propanediol. Isodolastatin H (15) is the structural isomer of dolasatin H (15), in which the tetrapeptide is esterified at the C-terminus by the secondary hydroxyl group of 3-phenyl-1,2-propanediol. The absolute stereochemistry of dolastatin H (14) and isodolastatin H (15) was unambiguously determined by the enantioselective total synthesis.