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

本研究对本课题组从海洋海绵和甲藻中分离得到的大环内酯类生物活性天然产物中的许多手性中心进行了绝对立体化学测定。1.茶酮内酯A是从冲绳海绵Theonella sp.中分离得到的一种新的细胞毒性37元大环内酯类化合物，具有独特的诱导兔血小板变形和聚集的生物活性。酮唑内酯A含有23个手性中心，其中末端位置(C-75)的一个手性中心的绝对构型根据降解产物的合成确定为R。对于大环内酯经臭氧化反应得到的C-4-C-17片段，模型化合物的合成结果表明，两个1，3-二醇型结构单元的相对构型均为同构体。因此，四种结构仍然是可能的，两种可能的非对映异构体被合成为光学活性形式。比较它们的光谱和光学数据，确定了C-4-C-17片段中包含的4个手性中心的绝对构型：8S，10R，14S，16S2。从该甲藻中分离出一种有效的细胞毒性大环内酯类化合物，并合成了其C-1-C-9片段的非对映异构体，为降解研究提供了可靠的样品。为了提供足够数量的天然产物用于降解实验，继续进行甲藻的进一步大规模培养。通过对该甲藻培养细胞提取物的进一步研究，分离得到两个新的大环内酯类化合物，分别为两性内酯R和S，并根据光谱数据和化学实验确定了它们的结构和绝对构型。

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.