以G-四链体为靶点运用NMR发现筛选民族药用木兰属植物中新型抗肿瘤先导化合物的研究

It remains a huge problem worldwide for us to discover novel anti-tumor drug which is highly effective and specifc. Natural products with novel structures, good biological ativity and drug potential are always adequate-quality source for anti-tumor lead compounds. However, traditional drugs designed on the structure and function of DNA duplex are extremely nonspecific and cytotoxic. Fortunately, due to their special structure and biologial roles, G-quadruplexes, a new secondary DNA structure, became a new effective target for anti-tumor drug screening. Furthermore, non cell-based NMR screening is a powerful and sensitive technique, which remarkbaly avoids redundancy caused by traditonal screening methods. Previous research in our group showed that a new lignan isolated from Magnolia liliflora is effective against UV damage on DNA. Accordingly, it is proposed to select three Magnolia plants used as drugs in ethnical area and never studied before as plant material, and select the human telomere DNA G-quadruplex as the anti-tumor activity target. The key technique we used to observe the interreaction between small molecules in the plant samples and the G-quadruplex is high-resolution NMR, which help us to screen G-quadruplex stabilizer quickly and efficiently. As a result, it is anticipated to discover novel anti-tumor lead compounds with high specificity and low toxicity from the three Magnolia plants. This project apply advanced achievement in life science and new progress in spectroscopic techniques to the research on plant secondary metabolites. It also provides a new idea and practices a new method for the modern research and development on traditional natural resources in ethnical area in China.

寻找高效低毒新型抗肿瘤药物是生命科学的重要课题。具有优良药效和成药性的天然产物始终是抗肿瘤先导化合物的优质来源。但以双链DNA为靶点研发的药物普遍选择性低、毒性强，DNA G-四链体的发现及生理功能揭示为寻找高效低毒抗肿瘤药物提供了有效新靶点。传统活性筛选法时间长，样品用量大显著降低了新药研发效率，先进的细胞外NMR筛选技术成功克服了传统方法的缺点。课题组前期实验发现一个木兰属植物中新的木脂素可有效对抗DNA紫外损伤，因此拟以3种尚未见研究的民族地区木兰属药用植物为筛选源，以人端粒DNA G-四链体为靶点，运用NMR技术跟踪样品与靶点的作用，高效筛选抗肿瘤先导化合物。本项目将生命科学前沿成果和光谱学技术新进展结合，快速灵敏寻找筛选成分复杂的植物样品中结构未知活性次级代谢产物，为特异性高、毒副作用小的抗肿瘤新药研发提供新型先导化合物，也为民族地区传统天然产物的系统研发提供新思路，探索新方法。

寻找高效低毒新型抗肿瘤药物是生命科学的重要课题。具有优良药效和成药性的天然产物始终是抗肿瘤先导化合物的优质来源。以双链DNA为靶点研发的药物普遍选择性低、毒性强，但DNA G-四链体的发现及生理功能揭示为寻找高效低毒抗肿瘤药物提供了有效新靶点。传统活性筛选法时间长，样品用量大显著降低了新药研发效率，先进的细胞外NMR筛选技术成功克服了传统方法的缺点，是寻找与生物大分子弱结合作用小分子配体的有力手段。本项目将生命科学前沿成果和光谱学技术新进展结合，以民族地区木兰科（Magnoliaceae）中，2种木兰属（Magnolia）、1种木莲属（Manglietia）以及1种八角属（Illicium Linn.）植物为筛选源，以人端粒DNA G-四链体为靶点，运用NMR技术跟踪样品与靶点的作用，从成分复杂的植物样品中发现并鉴定了71个化合物的结构，其中8个新化合物。综合运用CD、FRET、ITC和NMR，及计算机理论计算详细观测并分析了1个新木脂素与人端粒G-四链体的相互作用。项目研究为特异性高、毒副作用小的抗肿瘤新药研究提供了有价值的新分子实体，也为民族地区传统天然产物的系统研发提供新思路，探索新方法。