海洋微生物化学空间的拓展与抗癌先导化合物的高效发现

Natural products and their derivatives are the main source of the new drugs, of which marine natural products (MNPs) showed better druggability than their terrestrial counter parts. The nitrogen-containing and halogenated compounds are the main structure type of the drugs as well as the microbial MNPs. Our previous study showed that the staurosporine analogues and derivatives, one type of nitrogen-containing compounds belonged to indolocarbazole alkaloids from the marine actinobacteria, displayed anticancer activity both in vitro and in vivo against human acute myeloid leukemia (AML) with Flt3-ITD mutation (MV 4-11). Based on these findings, the chemical space of staurosporine derivatives will be fully expanded by means of microbial fermentation and chemical derivatization to obtain much more drug-like compounds. And then the anticancer activity of these compounds against the human acute leukemia will be assayed with tumor cells, molecular target proteins and nude mice. Furthermore, the structure-activity relationship against human AML and action mechanisms, for example Flt3-related signaling pathway, will also be investigated. The implementation of this project is expected to provide 2–3 new anticancer drug leads or candidates targeting Flt3, and thus to provide scientific evidences for the development of the new anticancer drugs.

天然产物及其衍生物是药物的主要来源，而海洋天然产物具有更大的成药性。含氮和卤代化合物是药物、也是海洋天然产物（特别是海洋微生物天然产物）的主要结构类型。申请者前期发现海洋放线菌产生的一类含氮化合物，即星孢菌素类生物碱，体外对肺癌A549细胞和人结直肠癌HCT-116细胞以及白血病细胞具有强的细胞增殖抑制活性、体内对人急性髓细胞性白血病AML（Flt3-ITD突变的MV4-11）具有优良的抑瘤活性。本项目拟在此基础上，通过微生物发酵与化学衍生的方法，充分拓展星孢菌素类生物碱的化学空间；用细胞、分子和体内模型研究星孢菌素类生物碱对白血病等恶性肿瘤的拮抗作用，进而揭示星孢菌素类生物碱抗肿瘤的构效关系，探讨其作用机制。获得2–3个具有成药前景、靶标明确的抗白血病新药先导物或的候选新药，为抗癌新药的研发提供科学依据。

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