Total structure determination of apratoxin A, a potent novel cytotoxin from the marine cyanobacterium Lyngbya majuscula
Total structure determination of apratoxin A, a potent novel cytotoxin from the marine cyanobacterium Lyngbya majuscula
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DOI：
10.1021/ja010453j
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发表时间：
2001-06-13
影响因子：
15
通讯作者：
Corbett, TH
中科院分区：
文献类型：
--
作者：
Luesch, H;Yoshida, WY;Corbett, TH
Apratoxin A（1）是从海洋蓝细菌Lyngbya majuscula Harvey ex Gomont中分离出的一种具有新骨架的强细胞毒素。这种混合肽-聚酮生物发生的环缩酚肽具有侧接聚酮部分的噻唑啉环，其中一个具有不寻常的甲基化模式。其总体结构已通过光谱分析，包括各种2D NMR技术阐明。氨基酸衍生单元的绝对构型通过水解产物的手性HPLC分析来确定。首次应用J构型分析方法，利用碳-质子自旋偶合常数（（2，3）J（C，H））和质子-质子自旋偶合常数（（3）J（H，H）），对新的二羟基脂肪酸单元3，7-二羟基-2，5，8，8-四甲基壬酸进行了相对立体化学分析;通过Mosher分析确定其绝对立体化学。1在溶液中的构象进行了模拟的分子模拟，采用距离几何和约束的分子动力学相结合。Apratoxin A（1）对人类肿瘤细胞系的体外细胞毒性IC 50值范围为0.36至0.52 nM;然而，它在体内对结肠肿瘤仅具有轻微活性，对乳腺肿瘤无效。
Apratoxin A (1), a potent cytotoxin with a novel skeleton, has been isolated from the marine cyanobacterium Lyngbya majuscula Harvey ex Gomont. This cyclodepsipeptide of mixed peptide-polyketide biogenesis bears a thiazoline ring flanked by polyketide portions, one of which possesses an unusual methylation pattern. Its gross structure has been elucidated by spectral analysis, including various 2D NMR techniques. The absolute configurations of the amino acid-derived units were determined by chiral HPLC analysis of hydrolysis products. The relative stereochemistry of the new dihydroxylated fatty acid unit, 3,7-dihydroxy-2,5,8,8-tetramethylnonanoic acid, was elucidated by successful application of the J-based configuration analysis originally developed for acyclic organic compounds using carbon-proton spin-coupling constants ((2,3)J(C,H)) and proton-proton spin-coupling constants ((3)J(H,H)); its absolute stereochemistry was established by Mosher analysis. The conformation of 1 in solution was mimicked by molecular modeling, employing a combination of distance geometry and restrained molecular dynamics. Apratoxin A (1) possesses IC50 values for in vitro cytotoxicity against human tumor cell lines ranging from 0.36 to 0.52 nM; however, it was only marginally active in vivo against a colon tumor and ineffective against a mammary tumor.