Synthesis and Biological Evaluation of Natural Product Analogues

描述（由申请人提供）：由于存在含有一种或多种溴酪氨酸残基的生物碱，从Verongida海绵中分离出的一系列海洋天然产品已被深入研究。许多生物碱代谢物在肿瘤细胞系中显示出有趣的生物活性和细胞毒性。天然产物11-脱氧瘘素-3对雌激素依赖性人乳腺癌细胞系MCF-7具有细胞毒性（LD50 = 17 mg/L）。由于乳腺癌是妇女中最常见的癌症，也是妇女癌症死亡的第二大原因，生物活性天然产品可以作为结构模板，用于构建更有效的合成类似物，作为乳腺癌的非手术治疗方法。这种天然产物的一个有趣的结构方面是存在两个螺旋环部分。这个研究项目有三个主要目标。第一个目标是开发一种可以应用于生物活性天然产物11-脱氧瘘管素-3的不对称全合成的合成方法。其次，我们计划构建天然产物的合成类似物，以确定天然产物的一个片段是否也能显示出对MCF-7细胞的生物活性。我们的最终目标是确定是否有任何MCF-7活性的合成类似物和天然产物可以有效地结合雌激素受体。从这些结合试验中产生的数据将导致对生物活性化合物和雌激素受体的配体-受体相互作用的理论对接研究，并且这些化合物的结构-活性关系谱的生成可能会导致比天然产物更有效的合成类似物。

DESCRIPTION (provided by applicant): A series of marine natural products isolated from the sponge of Verongida have been intensively studied due to the presence of alkaloids with one, or more bromotyrosine residues. Many of these alkaloid metabolites show interesting bioactivity and cytotoxic properties in tumor cell lines. The natural product, 11-Deoxyfistularin-3 is cytotoxic against the estrogen dependant human breast carcinoma cell line MCF-7 (LD50 = 17 mg/L). Since breast cancer is the most common cancer among women, and the second leading cause of cancer death for women, biologically active natural products can serve as a structural template for the construction of more potent synthetic analogues as a non-surgical treatment for breast cancer. One of the interesting structural aspects of this natural product is the presence of two spirocyclic moieties. This research project has three main objectives. The first objective is to develop a synthetic methodology that can be applied toward the asymmetric total synthesis of the biologically active natural product, 11-deoxyfistularin-3. Secondly, we plan to construct synthetic analogues of the natural product to determine if a segment of the natural product can also display biological activity against MCF-7 cells. Our final objective is to determine if any of the MCF-7 active synthetic analogues and the natural product can effectively bind to estrogen receptors. The data generated from these binding assays will lead to theoretical docking studies of the ligand-receptor interactions of the biologically active compound and the estrogen receptor, and the generation of a structure-activity relationship profile of these compounds could potentially lead to synthetic analogues that are more potent than the natural product. PUBLIC HEALTH RELEVANCE: We are investigating a method to make potent compounds to target breast cancer which is the second leading cause of cancer death in women. The compounds that we are targeting are based upon a naturally occurring substance found in the ocean.