Synthesis and Biological Evaluation of Natural Product Analogues

描述(申请人提供)：由于存在含有一个或多个溴酪氨酸残基的生物碱，从维龙吉达海绵中分离出的一系列海洋天然产物已被深入研究。其中许多生物碱代谢产物在肿瘤细胞系中表现出有趣的生物活性和细胞毒活性。天然产物11-脱氧瘘菌素-3对雌激素依赖的人乳腺癌细胞株MCF-7具有细胞毒作用(LD_(50)=17 mg/L)。由于乳腺癌是女性最常见的癌症，也是女性癌症死亡的第二大原因，生物活性天然产物可以作为构建更有效的合成类似物的结构模板，作为乳腺癌的非手术治疗。这种天然产物的一个有趣的结构方面是存在两个螺环部分。这项研究项目有三个主要目标。第一个目标是开发一种合成方法，可以应用于生物活性天然产物11-脱氧瘘草素-3的不对称全合成。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部分是否也可以显示出对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活性合成类似物和天然产物能够有效地与雌激素受体结合。这些结合分析产生的数据将导致对具有生物活性的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-活性关系曲线的产生可能导致合成比天然产物更有效的类似物。 与公共卫生相关：我们正在研究一种方法，以制造有效的化合物来靶向乳腺癌，乳腺癌是女性癌症死亡的第二大原因。我们瞄准的化合物是基于海洋中发现的一种自然存在的物质。

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.