黔产藤黄科植物中靶向溶酶体的抗肿瘤活性成分研究

Searching for the antineoplastic drugs with high efficiency and low toxicity from natural products has become a hot area in the world. The latest research revealed that the formation and development of tumor have a close relationship with autophagy, and lysosomes are key organelles of autophagy. So, targeted cancer therapy might be realized by affecting the function of lysosome. In our previous research, a series of novel polyprenylated benzophenones (PPBS) with good antitumor activity were isolated from the antitumor crude extracts of Garcinia multiflora and Hypericum japonicum (Guttiferae) of medical plants from Guizhou Province. In addition, a new PPBS showed good antitumor activity by effecting the acidification of lysosome in HeLa cell. We plan to investigate the chemical constituents especially PPBS of the two plants and evaluate the antitumor activity of targeted lysosome of the isolates. Meanwhile, the structure-activity relationship will be discussed on the basis of structural modification. Furthermore, we plan to further investigate how these compounds function in the process of tumor autophagy by identifying their target proteins and/or signaling pathways, which could lay a solid foundation in discovering targeted antineoplastic drugs.

从天然产物中寻找高效、低毒的抗肿瘤药物一直都是国内外的研究热点。最新研究表明，细胞自噬的程度与肿瘤的发生、发展密切相关，而溶酶体是细胞自噬的关键细胞器，因此干预溶酶体的功能有望成为靶向治疗肿瘤的新方法。前期研究中，我们首次从具有抗肿瘤活性的黔产藤黄科药材木竹子(Garcinia multiflora)和田基黄(Hypericum japonicum)的提取物中发现了一类骨架新颖的多异戊烯基二苯甲酮类(PPBS)分子，且具有较好的肿瘤抑制活性，进一步研究表明其中一个新骨架的PPBS分子可能是通过影响肿瘤细胞溶酶体的酸化来达到抗肿瘤效果。本课题拟在此基础上对木竹子和田基黄进行系统的化学成分研究，以其中PPBS类成分为主要研究对象，开展靶向溶酶体的抗肿瘤活性及其构效关系研究，并对其作用机制进行初步探讨，为发现靶向抗肿瘤新药候选化合物提供科学基础。

从天然产物中寻找高效低毒的抗肿瘤药物一直都是国内外的研究热点。本项目对黔产藤黄科两种药用植物木竹子(Garcinia multiflora)和田基黄(Hypericum japonicum)的化学成分进行研究，运用NMR、X-ray单晶衍射、量子化学计算、手性HPLC拆分等手段共分离鉴定化合物115个，新骨架类型化合物10个，7对外消旋体。此外，通过对其中一个高含量的PPBS进行骨架转化及结构修饰得到衍生物40个。本研究首次从藤黄科植物中发现了外消旋体和光学体共存的现象，当一个异戊烯基的为末端双键时为光学体，当异戊烯基的为非末端双键时为外消旋体，该现象在天然产物中极其少见；此外我们也提出了合理的生源合成途径解释了这一现象产生的原因。经抗肿瘤活性筛选，发现大部分化合物具有较好的抗肿瘤活性，对部分化合物进行了初步作用机制研究，研究发现一个PPBS具有较好的影响肿瘤细胞溶酶体酸化的作用；其他活性较好的化合物通过多种作用途径产生良好的抗肿瘤活性，包括影响白血病细胞的原癌基因（Fli-1）的活性、影响肿瘤细胞周期及诱导肿瘤细胞凋亡。