Studies on the stereochemistry of new macrolides from marine organisms for research and development of drug molecules

海洋生物新大环内酯的立体化学研究，用于药物分子的研发

基本信息

批准号：
07558208
负责人：
ISHIBASHI Masami
金额：
$ 2.05万
依托单位：
CHIBA UNIVERSITY (1997)Hokkaido University (1995-1996)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07558208/
关键词：
Marine natural products Macrolide Sponge Dinoflagellate Stereochemistry Chiral carbon Synthesis Structure elucidation 過鞭毛藻

项目摘要

In this research project, we investigated on determination of absolute stereochemistry of many chiral centers contained in bioactive marine natural products classified as macrolides, which were isolated from marine sponges and dinoflagellates by our research group.1.Theonezolide A is a novel cytotoxic 37-membered macrolide isolated from the Okinawan marine sponge Theonella sp., having unique bioactivity of induction of rabbit platelet shape change and aggregation. Theonezolide A contains 23 chiral centers, among which the absolute configuration of one chiral center at the terminal position (C-75) was determined as R on the basis of synthesis of a degradation product. As to the C-4-C-17 fragment, which was obtained by ozonolysis of the macrolide, the relative configurations of two 1,3-diol type moieties were suggested as both syn from the synthesis of model compounds. Four structures therefore remained to be likely, and two possible diastereomers were synthesized as optically active forms. Comparison of their spectral and optical data established the absolute configuration of four chiral centers contained in the C-4-C-17 fragment as 8S,10R,14S,16S.2.Amphidinolides are unique macrolides obtained from cultured marine dinoflagellate Amphidinium sp. A diastereomer of the C-1-C-9 fragment of amphidinolide C,one of the potent cytotoxic macrolides isolated from this dinoflagellate, was synthesized to provide an authentic sample for the degradation studies. To provide an adequate quantity of the natural product to supply for degradation experiments, further large-scale culturing of the dinoflagellate Amphidinium sp.was continued. During further examinations on the extracts of the cultured cells of this dinoflagellate, two new macrolides, amphidinolides R and S,were isolated and their structures including absolute configuration were elucidated on the basis of spectroscopic data as well as chemical experiments.

在本研究项目中，我们研究组从海绵和甲藻中分离出大环内酯类具有生物活性的海洋天然产物中所含的许多手性中心的绝对立体化学。 1. Theonezolide A是一种新型的细胞毒性37元化合物从冲绳海绵 Theonella sp. 中分离出的大环内酯，具有诱导兔血小板形状改变和聚集的独特生物活性。 Theonezolide A含有23个手性中心，其中末端位置(C-75)的1个手性中心的绝对构型根据降解产物的合成确定为R。对于通过大环内酯的臭氧解获得的C-4-C-17片段，两个1,3-二醇型部分的相对构型从模型化合物的合成中被建议为顺式。因此，四种结构仍然是可能的，并且两种可能的非对映异构体被合成为光学活性形式。对其光谱和光学数据的比较确定了 C-4-C-17 片段中包含的四个手性中心的绝对构型为 8S、10R、14S、16S。2。Amphidinides 是从培养的海洋甲藻 Amphidinium sp 中获得的独特大环内酯。合成了两栖内酯 C 的 C-1-C-9 片段的非对映异构体，这是从这种甲藻中分离出的一种有效的细胞毒性大环内酯，为降解研究提供了真实的样品。为了提供足够数量的天然产物用于降解实验，继续大规模培养甲藻Amphidinium sp.。在对该甲藻培养细胞提取物的进一步检查中，分离出两种新的大环内酯类，两栖类内酯类R和S，并根据光谱数据和化学实验阐明了它们的结构，包括绝对构型。