49(P-9) ヤドクガエルAtelopus zetekiの毒zetekitoxinの訂正構造とNa^+チャンネル阻害活性(ポスター発表の部)

概要

論文の詳細を見る
Zetekitoxin (ZTX,1) was first reported in 1969 as a potent toxin from the Panamanian frog, Atelopus zeteki. Working on a small sample (approx. 300μg), we previously reported the relative stereostructure of 1 on the 42nd symposium (Okinawa, 2000). However, we found a discrepancy in its spectral data, and revised the structure of 1. Here we report the revised structure of 1, and its significantly higher activity to inhibit sodium channel than 2. In the previous structure of 1, the relative configuration of C6 was suggested to be different from that of 2. However, the C2/H6 and C4/H6 cross peaks were shown on HMBC spectrum of 1, similar to those of the analogs of 2 newly measured, suggesting that the relative configuration of C6 of 1 was same as that of 2, and the previous structure was ruled out. The backbone structure of 2 in 1 and the presence of the additional N7 substituent in 1 were confirmed by cross peaks on ^<15>N-^1H HMBC spectrum. The structure of the N7 substituent was suggested to be CH_2OCONHOH by ^<13>C-^1H HMBC correlation of H19b/C20, and by comparison of the fragmentation pattern on ESI-MS/MS between 1 and some model compounds which had the N-CH_2-O-carbamoyl moieties. C13 (156.4) and C15 (53.7) could be connected via N based on their ^<13>C chemical shifts, although this connectivity was not proved by the HMBC data. Two hydroxy methylene at C18 and C17 were suggested to be CH_2OH and CH_2OSO_3H, respectively, by the isotope shift observed at C18, and the typical chemical shifts of 17-CH_2 (68.9, 4.25, 4.26) for CH_2OSO_3H. To assemble the structure by the remaining atoms to satisfy the molecular formula, the connectivity of C13(C15)-N-O-C12 was plausible, since only 12β-OH was possible to make a bond with amide N. Thus, we propose the revised structure of 1 which possesses an unique hydroxyamine hemiacetal, and an N-hydroxy carbamate. The NOESY and ROESY correlations H15/H10β, H14α/H10β, H17/H14α, and H15/H16 in addition to ^3J_<H15/H16> 7.7Hz, indicated that C17 and C14, and H15 and H16 were syn in the major conformers, and suggested the relative configurations at C11, C15, and C16. IC_<50> of 1 to human heart, brain IIa, and rat skeletal muscle sodium channels expressed in Xenopus oocytes were determined by measurement of currents by two-electrode voltage clamp. IC_<50> were determined at 278, 6.1, and 65pM respectively, 540, 340, and 48 times smaller than those of 2, suggesting that 1 is the most potent sodium channel inhibitor ever known.
天然有機化合物討論会の論文
2002-09-01

49(P-9) ヤドクガエルAtelopus zetekiの毒zetekitoxinの訂正構造とNa^+チャンネル阻害活性(ポスター発表の部)

スポンサーリンク

概要

著者

関連論文

スポンサーリンク