海洋天然产物是抗肿瘤药物开发的重要源泉。Marmycin A是2007年文献报道的结构独特和抗肿瘤活性明显的蒽醌类海洋天然产物。申请人课题组2009年首次报道了去甲基天然产物类似物的全合成（J Org Chem-2009-6111），并通过进一步衍生化（Adv Syn Catl-2010-847）和活性筛选，发现部分化合物显示了一定的抗癌活性和酪氨酸激酶靶向性。本项目将在此基础上，一方面通过探索新的合成方法进一步进行Marmycin A的全合成研究；另一方面将通过分子碎片化和重组装、环系增减、官能团嵌入、药效团跃迁、生物电子等排置换等药物结构优化策略建立聚焦型类天然产物库和天然产物衍生物库，以提高化合物的抗癌活性和成药性（ADMET），并通过细胞和分子水平活性评价以及作用机制的阐释，获得1-2个具有明显抗肿瘤活性的候选药物,为进一步研发具有自主知识产权的新药奠定基础。

Marine natural products are important source of antitumor drug development. Marmycin A is a marine natural product isolated in 2007 by Fenical et al bearing unprecedented structural features containing both C- and N-glycosidic bonds forming into a hexacyclic framework. More importantly, marmycin A was reported having significant cytotoxicity against several cancer cell lines, especially human colon carcinoma cell line HCT-116 with an IC50 value of 60.5 nM. Accordingly, the structural complex Marmycin A has become a challenging target for total synthesis and an attractive startpoint for drug design and development. In 2009, our group reported the first total synthesis study on Marmycin A and built up a small library of 3'-desmethyl analogues. Preliminary biological study indicated that these des-methyl analogues showed moderate cytotoxicity against several cancer cell lines, and several compounds have somewhat inhibitory effects against receptor tyrosine kinase (RTK). In this regard, several new practical synthetic routes have been designed in this proposal and further efforts will be conducted towards the completion of total synthesis of the natural product. Meanwhile, medicinal chemistry approaches including strategic incorporation of target-based privileged structure, bioisosteric replacement and pharmacophore hopping, will be applied to construct natural product derivatives with more structural diversity and better druggability. The new compounds will be evaluated both in vitro and in vivo. Compounds with significant cell proliferative inhibition will be further evaluated in the pharmacokinetic and in vivo mouse model studies. All these findings will be used for further structural modification to optimize the antitumor efficacy and the safety parameters and finally generate 1-2 lead compounds for further antitumor drug development.