具有抗肿瘤活性天然产物Marmycin A的全合成、衍生化及生物活性研究

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.

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。

天然产物Marmycin A是一类结构新颖的具有抗肿瘤活性的桥状糖苷内化合物，本项目通过对其主体骨架全合成、衍生化，并借助文献报道的靶向性抗肿瘤药物药效结构，通过骨架融合和跃迁，借助天然产物优势骨架以及药物化学骨架跃迁及药效团融合等技术，构建200余个天然产物类似物和衍生物。 通过对细胞毒和肿瘤依赖的激酶谱筛选，获得了结构新颖高活性的渐变性淋巴瘤激酶ALK抑制剂化合物II，对ALK野生型和L1196M突变的半数抑制常数分别为3.4 nM和3.9 nM，对ALK阳性非小细胞肺癌细胞H3122的增殖抑制为17.9 nM。化合物II具有较好选择性，对其它相近的激酶活性较弱，在大鼠体内的药代性质良好，生物利用率达67%。体内实验显示，化合物II对NIH/3T3小鼠移植瘤的生长抑制作用明显，在20 mg/kg和40 mg/kg每天一次口服给药剂量下，使用20 mg/kg和40 mg/kg每天一次剂量治疗后，对应的肿瘤模型生长完全停止 (抑瘤率>100%)，并且肿瘤部分消退，表现出显著的肿瘤生长抑制效果。在NIH/3T3-EML4-ALK (L1196M) 移植瘤耐药模型中，化合物II以40 mg/kg 给药剂量治疗后，也能够使肿瘤停止增长和肿瘤的部分消退。因此，化合物II具有较好的体内外抗肿瘤活性，具有进一步开发价值。项目执行期间，发表标注本基金的SCI论文26篇，申请国家发明专利10项。培养博士研究生5名，联合培养博士生3名，联合培养硕士3名。

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