The Synthesis and Bioassay of Novel Pyrroles

描述(由申请人提供)：本提案是根据美国国立卫生研究院面积拨款CA 67236-04发起的工作的继续。来自海洋的天然产品仍然是具有生物意义的化合物的丰富来源，特别是含有吡咯的海洋天然产品显示出作为抗肿瘤药物、多药耐药逆转剂、血管干扰剂和艾滋病毒整合酶抑制剂的活性。这些含有吡咯的天然产物的特征通常是连接在吡咯环体系的碳3和碳4上的高氧苯基或杂环基团，以及位于碳2和/或碳5上的含有羰基的官能团。我们已经建立和正在开发的合成方法允许快速构建高取代和高官能化的吡咯。这种方法还允许结构活性关系(SAR)研究的结构多样性，这可能导致化疗药物具有更强的效力和减少毒副作用。为新的供资周期提出的工作将包括应用我们的合成方法以及一些新的和补充的方法来合成海洋天然产物葡萄糖酸、葡萄糖素B、葡萄糖素C、葡萄糖素E和相关化合物，例如JG-03-14的新类似物。JG-03-14是一种有趣的合成吡咯，它是从我们的研究努力中出现的，并已在体外显示出对乳腺癌细胞株的活性(IC50为35 NM)，并在体内对小鼠前列腺癌异种移植瘤具有活性。JG-03-14还被证明对耐药的乳腺癌细胞株具有活性，是微管蛋白聚合的抑制剂，是血管干扰剂和自噬细胞死亡的促进剂。我们目前和不断发展的合成方法将使我们能够将我们的目标扩展到这些重要的生物活性、天然产品和新的JG-03-14类似物。所有的目标分子、它们的前体和它们的类似物都将由一个经验丰富的合作者团队进行生物学评估，这些研究将与另一位合作者的分子建模相结合。由于我们的项目包括合成、生物测定和分子建模驱动的SAR，我们相信从这些研究中很可能会出现一种新的和可行的癌症化疗临床候选方案。 公共卫生相关性：针对特定疾病状态的新的和新的化疗药物的开发在很大程度上仍然依赖于“先导化合物”的发现，这种化合物可以进一步开发为可行的候选药物。天然化合物仍然是“药物先导”的主要来源，我们目前的建议是利用我们的吡咯形成反应来合成具有生物意义的天然产物，如没食子酸、没食子酸B和C、来那霉素E和相关化合物。除了这些天然产品目标外，我们还将继续开发我们的合成吡咯的新衍生物JG-03-14，它继续显示出良好的生物学特性。大多数这些天然产物、它们的类似物和前体以及JG-03-14类似物将由一个经验丰富的合作者团队进行生物评估和计算建模。

DESCRIPTION (provided by applicant): This proposal represents a continuation of work initiated under NIH AREA grant CA 67236-04. Natural products of marine origin continue to be a rich source of biologically interesting compounds and pyrrole containing marine natural products in particular have demonstrated activity as anti-tumor agents, multidrug resistant reversal agents, vascular disrupting agents and inhibitors of HIV integrase. These pyrrole containing natural products are usually characterized by highly oxygenated phenyl or heterocyclic groups attached at carbons 3 and 4 of the pyrrole ring system along with carbonyl containing functionality located at carbons 2 and/or 5. The synthetic methodology that we have established and are developing allows for rapid construction of highly substituted and highly functionalized pyrroles. This methodology also allows for great structural diversity for structure activity relationship (SAR) studies, which could lead to chemotherapeutic agents with increased potency and decreased toxic side effects. Work proposed for the new funding cycle will involve applying our synthetic methodology along with some new and complimentary methodology to the synthesis of the marine natural products lycogallic acid, lycogarubin B, lycogarubin C, lynamycin E and related compounds, such as new analogs of JG-03-14. JG-03-14 is an interesting synthetic pyrrole, which has emerged from our research efforts, and has demonstrated in vitro activity (IC50 of 35 nM) against breast cancer cell lines and in vivo activit against a mouse prostate cancer xenograft. JG-03-14 has also been shown to be active against drug resistant breast cancer cell lines, an inhibitor of tubulin polymerization, a vascular disrupting agent and a promoter of autophagic cell death. Our current and evolving synthetic methodologies will allow us to extend our targets to these important bioactive, natural products and new JG-03-14 analogs. All of the target molecules, their precursors and their analogs will be subject to biological evaluation by a team of highly experienced collaborators and such studies will be coupled with molecular modeling by an additional collaborator. Since our project encompasses synthesis, bioassay and molecular modeling driven SAR, we believe that a novel and viable clinical candidate for cancer chemotherapy may well emerge from such studies. PUBLIC HEALTH RELEVANCE: The development of new and novel chemotherapeutic agents for a particular disease state continues to depend to a significant degree on the discovery of a "lead compound", which can be further developed into a viable drug candidate. Naturally occurring compounds continue to be a major source of "drug leads" and our current proposal seeks to utilize our pyrrole forming reactions to synthesize biologically interesting natural products such as lycogallic acid, lycogarubins B and C, lynamycin E and related compounds. In addition to these natural product targets, we will continue to develop new derivatives of our synthetic pyrrole, JG-03-14, which continues to exhibit promising biological properties. The majority of these natural products, their analogs and precursors along with JG-03-14 analogs will be biologically evaluated and computationally modeled by a team of highly experienced collaborators.