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)。世界卫生组织(WHO)最近预测，到2030年，癌症导致的死亡人数预计将增加到1310万人。在所有其他致命癌症中，浸润性乳腺癌是女性中最常见的恶性肿瘤(在美国和欧洲分别为31%和27%)，是仅次于肺癌的第二大癌症相关死亡原因。在美国，女性一生中罹患乳腺癌的风险为32%，患乳腺癌导致死亡的风险为15%。我们计划通过开发天然产物11-脱氧呋喃舒林-3的衍生物来解决改善上述统计数据的挑战，这种天然产物将对MCF-7乳腺癌具有亚微摩尔活性。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，这些化合物的结构-活性关系曲线的产生可能导致构建具有亚微摩尔活性的合成类似物对乳腺癌细胞的活性。

 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 cytotoxi against the estrogen dependant human breast carcinoma cell line MCF-7 (LD50 = 17 mg/L). The World Health Organization (WHO) recently predicted that death caused by cancer is expected to increase to 13.1 million by 2030. Among all other deadly cancers, invasive breast cancer is the most recurrently diagnosed malignant tumor among women (31% in the US and 27% in Europe) and the second leading cause of cancer related death subsequent to lung cancer. Women have a 32% lifetime risk of developing breast cancer and 15% risk of breast cancer causing death in the US. We plan to address the challenge of improving the aforementioned statistics through developing derivatives of the natural product, 11-deoxyfustularin-3, that will have sub-micromolar activity against MCF-7 breast cancer. 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 the construction of synthetic analogues that possess sub-micromolar activity against breast cancer cells.