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Research for dinoflagellates producing cytotoxic macrolide using DNA probes and development of leads for anticancer drugs

利用DNA探针研究产生细胞毒性大环内酯的甲藻和抗癌药物先导化合物的开发

基本信息

批准号：
16510153
负责人：
TSUDA Masashi
金额：
$ 2.5万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16510153/
关键词：
macrolide dinoflagellate cytotoxic 抗腫瘍性遺伝子プローブ迅速探索法

项目摘要

In our searches for bioactive metabolites from marine dinoflagellates, we have isolated a series of cyototoxic macrolides, named amphidinolides, from marine symbiotic dinoflagellates Amphidinium species separated from acoel flatworms Amphiscolops species. Amphidinolides exhibit potent cytotoxicity and antitumor activity. Nevertheless, Amphidinium species with producing ability of bioactive substances such as macrolides or long-chain polyketides are difficult to discriminate acutely and conventionally by light microscopic observation. Development of the conventional method for identification and screening of Amphidinium species to produce these secondary metabolites was useful. In this study, the molecular phylogenetic investigations of Okinawan Amphidinium dinoflagellates producing bioactive secondary metabolites such as cytotoxic macrolides were examined on the basis of nuclear-encoded partial small subunit (SSU) rDNA. Furthermore, specific DNA probes were developed from 18S rDNA sequences of the Amphidinium species producing cytotoxic macrolides, and we represent the first attempt to apply molecular probes for the discrimination of dinoflagellates producing bioactive substancesDuring our continuing search for bioactive substances from marine dinoflagellates, new cytotoxic 25-membered macrolides, amphidinolide C2 have been isolated from a marine dinoflagellate Amphidinium sp.(strain Y-72). On the other hand, two new potent cytotoxic macrolides, amphidinolides B4 and B5, have been isolated from a marine dinoflagellate Amphidinium sp.(strain Y-100) separated from marine flatworm Amphiscolops sp.Solution conformation of antitumor macrolide amphidinolide H in chloroform and dimthyl sulfoxide wer investigated on the basis of NMR data.

在研究海洋甲藻生物活性代谢产物的过程中，我们从海洋共生甲藻Amphidinium中分离出一系列具有细胞毒性的大环内酯类化合物，命名为amphidinolides。环己内酯类化合物具有很强的细胞毒性和抗肿瘤活性。然而，前沟藻物种的生物活性物质，如大环内酯类或长链聚酮化合物的生产能力是很难区分急性和常规的光学显微镜观察。发展用于鉴定和筛选前沟藻物种以产生这些次级代谢产物的常规方法是有用的。在这项研究中，分子系统发育的冲绳Amphidiniumdinoflagellates生产生物活性的次生代谢产物，如细胞毒性大环内酯类的核编码的部分小亚基（SSU）rDNA的基础上进行了研究。111在对海洋甲藻生物活性物质的研究中，我们从一种海洋甲藻Amphidinium sp.中分离到了一种新的具有细胞毒性的25元大环内酯化合物Amphidinium C2。（菌株Y-72）。另一方面，两个新的有效的细胞毒性大环内酯，amphidinolides B4和B5，已从海洋甲藻Amphidinium sp.（Y-100菌株）的NMR数据，研究了抗肿瘤大环内酯双端环内酯H在氯仿和二甲基亚砜中的溶液构象。