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

本课题主要研究了本课题组从海绵和甲藻中分离得到的具有生物活性的大环内酯类化合物中手性中心的绝对立体化学。1. Theonezolide A是从冲绳海绵Theonella sp.中分离得到的一种新的具有细胞毒性的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。Theonezolide A含有23个手性中心，其中在末端位置（C-75）的一个手性中心的绝对构型是基于降解产物的合成确定为R。对于臭氧分解大环内酯得到的C-4-C-17片段，通过模型化合物的合成，提出了两个1，3-二醇型结构部分的相对构型均为syn。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。2. Amphidinolides是从海洋甲藻Amphidinium sp.中分离得到的一种独特的大环内酯类化合物。Amphidinolides C-1-C-9片段的非对映异构体，是从该甲藻中分离得到的一种具有强烈细胞毒性的大环内酯类化合物。为降解研究提供真实样品。为了提供足够量的天然产物以供应降解实验，继续进一步大规模培养甲藻前沟藻。在进一步研究该甲藻培养细胞提取物的过程中，分离到两个新的大环内酯类化合物，ampidinolides R和S，并根据光谱数据和化学实验确定了它们的结构，包括绝对构型。

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.