Chemistry and Biology of Antitumor Natural Products

我们的研究计划的广泛目标是研究结构独特的 最终显示出对实体人类肿瘤细胞系具有不同细胞毒性的天然产物 为临床前评估提供与癌症生物学和潜在先导化合物相关的新见解 对抗实体人类肿瘤。这一续订申请特别侧重于小说的合成 天然产物Psymberin/Irciniastatin和Palmerolide。Psymberin/Irciniastatin是相关的代谢物 从海绵中分离出来的。据报道，它们能有效地抑制实体人类肿瘤细胞的生长。 台词。从结构上讲，它们与Pederin/mycalide家族的蛋白质合成抑制剂有关，但不同于 后者，psymberin在癌细胞系中显示出前所未有的差异性细胞毒性。我们提出了一个 全合成Psymberin/Irciniastatin，其类似物，以及用于作用模式研究的探针试剂。 我们还将开发新的化学方法来制备类似麦卡利胺的化合物，以便与 Psymberin，以充分剖析蛋白质合成抑制和分化的结构决定因素 细胞毒性。这些研究将为铅的识别和临床前研究提供坚实的基础 人类癌症治疗领域，并提供了适用于其他生物相关的化学方法学 抗癌天然产品。此外，我们还提出了一种新的高度收敛和适应性强的全局优化算法。 从南极被衣藻中分离出的化合物棕榈内酯的合成。Palmerolide展示了一种独特的 抑制选定黑色素瘤的NCI‘s 60细胞系人类肿瘤的不同细胞毒性图谱 与其他细胞系相比，敏感度高三个数量级的细胞系。这表明一个 潜在的新作用模式和起点--开发帕美洛里德作为药物的先导 治疗黑色素瘤癌症。我们的合成研究将提供进入综合化学品的第一条途径 对这种独特的抗癌天然产品进行生物学评价。 与公共健康相关：大多数获得FDA批准或处于高级临床阶段的抗癌药物 研究是基于天然产品的线索。我们的研究将深入研究新的天然产品 具有抗癌活性。我们将开发这些天然产物和合成类似物的高效合成 目的：寻找治疗人类肿瘤的抗癌药物。

The broad objective of our research program is to investigate the chemistry and biology of structurally unique natural products that show promising differential cytotoxicity against solid human tumor cell lines, ultimately providing new insights related to cancer biology and potential lead compounds for preclinical evaluation against solid human tumors. This renewal application specifically focuses on the synthesis of the novel natural products Psymberin / Irciniastatin and Palmerolide. Psymberin / Irciniastatin are related metabolites isolated from marine sponges. They were reported to potently inhibit the growth of solid human tumor cell lines. Structurally, they relate to the pederin / mycalamide family of protein synthesis inhibitors, but unlike the latter, psymberin displayed an unprecedented differential cytotoxicity among cancer cell lines. We propose a total synthesis of Psymberin / Irciniastatin, analogs thereof, and probe-reagents for mode-of-action studies. We also will develop novel chemistry to prepare Mycalamide-like compounds for direct comparison with Psymberin in order to fully dissect the structural determinants for protein synthesis inhibition and differential cytotoxicity. These studies will provide a solid foundation for lead identification and preclinical studies in the area of human cancer treatment, and provide chemical methodology applicable to other biologically relevant anticancer natural products. In addition, we also propose a novel highly convergent and adaptable total synthesis of Palmerolide, a compound isolated from an Antarctic tunicate. Palmerolide displayed a unique differential cytotoxicity profile in the NCI's 60 cell line panel of human tumors, inhibiting selected melanoma cell lines with three orders of magnitude greater sensitivity relative to other cell lines. This indicates a potential novel mode-of-action and starting point for the development of Palmerolide as a lead for the treatment of melanoma cancer. Our synthetic studies will provide the first entry into an integrated chemical biological evaluation of this unique anticancer natural product. Relevance to public health: A majority of anticancer drugs that are FDA approved or in advanced clinical studies are based on natural product leads. Our research will thoroughly investigate novel natural products with anticancer activity. We will develop efficient syntheses of these natural products and synthetic analogs to identify anticancer leads for the treatment of human tumor cancers.