基于深海功能基因的活性化合物及其形成机制研究

Isolation, structural elucidation and study of anti-tumor activity of secondary metabolites from six deep-sea environmental metagenomic libraries clones is carried out based on the retinoid X receptor alpha (RXRα) drug target. Through full length sequencing of these clones, functional gene clusters are identified, and new structural diversity in these metabolites, chemical mechanism, biosynthesis, and functional gene clusters of products of secondary metabolism are investigated. Metagenomics is seen as one of the most promising directions for the identification of new natural products with desired biological activities. One focus of our research program is to obtain new functional gene clusters and lead compounds on the discovery of new clone secondary metabolic processes by using both the sequenced genomes of cultured clones and the new secondary metabolites. The biological genetic resources show the great practical and scientific importance. We are currently using this approach on biosynthetic pathways to develop new anti-tumor drugs.

基于核受体RXRα为靶点，针对已知基因序列的六个深海宏基因组克隆子，开展抗肿瘤活性化合物的发现、优化及分子机制研究。利用深海特色功能基因的优势，研究活性次生代谢产物的结构特点、形成规律、生物合成基因和生物合成途径。课题将围绕着携带功能基因的深海宏基因组克隆子特有的次生代谢过程，获取一些新基因和活性先导化合物资源，阐明具有新颖结构的次生代谢产物的生物合成机制，发展天然药物化学研究新技术，为组合生物合成和新药设计奠定基础。

本课题基于主要源于深海的克隆子及相关深海微生物开展抗肿瘤活性物质分离、结构鉴定、先导化合物合成及活性评价研究。取得的主要结果如下：（1）完成了深海五株真菌次生代谢产物的分离、鉴定及活性研究；（2）完成了深海细菌次生代谢产物的分离、鉴定及B5抗炎活性研究，以及该菌株全基因组测序、等离子突变及突变克隆子文库的建立；（3）完成了深海宏基因组库25克隆子D7和10-1克隆子次生代谢产物的分离鉴定、活性研究和生物合成途径研究；（4）发展了快速分离微量混合物的多维制备液相色谱新方法；（5）完成了吲哚类化合物和黄酮衍生物的设计、合成及抗肿瘤活性研究，以及靶向RXR分子机制研究。