安莎类化合物属于I型聚酮，其成员大多具有广泛的生理活性，成药率高。前期研究中，本课题组从海洋放线菌中分离得到了9个新安莎，其中NA1是新骨架萘醌类安莎。初步生物学实验表明，NA1可能激活NADPH氧化酶(NOXs)诱导MDA-MB-435细胞产生活性氧(ROS)，从而引起细胞G2/M期停滞和凋亡。众所周知，活性天然产物由于溶解性、生物利用度和毒副作用等局限，成药性不理想。本项目将力图阐明NA1诱导ROS产生的机制；并针对成药性进行NA1的结构优化。首先明确NA1激活NOXs的作用靶蛋白；其次合成8个系列约300个NA1衍生物；然后对目标分子进行细胞、分子和实验动物水平上的活性筛选，以期发现2-3个活性强、选择性高的衍生物；最后开展2-3个NA1衍生物的成药性初步评价，为研发新型、高效低毒的安莎类抗肿瘤候选药物奠定基础，对肿瘤的预防和治疗具有重要意义。

Ansamycins belong to type I polyketides. Most members of this family have broad bioactivities, which afford high ratios of new drugs. Previously, our group isolated nine new ansamycins from marine Actinomycetes. Among these compounds, NA1 is a new backbone naphthoquinone-type ansamycin. Our preliminary biological experiments indicated that NA1 induced G2/M cell cycle arrest and apoptosis in MDA-MB-435 cells through activating NOXs to generate reactive oxygen species (ROS). It is well known that the druggability of bioactive natural products is not desirable due to the limits of solubility, bioavailability and side effects. Therefore, this project is going to investigate the mechanism of action of NA1 inducing the production of ROS, and to design and synthesize potent derivatives of NA1 with good druggability. Firstly, it should be defined the main cellular target of NA1 in activating NOXs. Then, NA1 will be structurally modified and optimized to afford a focus chemical library containing more than 300 compounds. Thirdly, these compounds will be screened by various bioassays at the levels of molecule, cell and animal tests, which will afford 2-3 potent antitumor derivatives of NA1 with high specificity. Finally, the druggability of 2-3 potent antitumor derivatives will be studied, which shall put forward a base for the drug development of ansamycins, and be significant to prevention and chemotherapy of oncology.