Chemistry and Biology of Antitumor Natural Products

描述(申请人提供)：我们研究计划的广泛目标是研究结构独特的天然产物的化学和生物学，这些天然产物对实体人类肿瘤细胞株显示出有希望的不同细胞毒性，最终为治疗实体人类肿瘤的临床前评估提供与癌症生物学相关的新见解和潜在的先导化合物。这一更新应用特别侧重于合成新型天然产物Psymberin/Irciniastatin和Palmerolide。Psymberin/Irciniastatin是从海绵中分离出来的相关代谢物。据报道，它们能有效地抑制实体人类肿瘤细胞系的生长。在结构上，它们与Pederin/mycalide家族的蛋白质合成抑制剂有关，但与后者不同的是，psymberin在不同的癌细胞系中表现出前所未有的差异性细胞毒性。我们建议全合成Psymberin/Irciniastatin及其类似物，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麦卡酰胺类化合物，以便与Psymberin进行直接比较，以便充分剖析蛋白质合成抑制和不同细胞毒性的结构决定因素。这些研究将为铅的鉴定和人类癌症治疗领域的临床前研究提供坚实的基础，并为其他具有生物相关性的抗癌天然产物提供化学方法学。此外，我们还提出了一种新的高度收敛和适应性强的棕榈内酯的全合成方法，这是一种从南极被衣藻中分离出来的化合物。Palmerolide在NCI的人类肿瘤60细胞系小组中显示出独特的差异性细胞毒性曲线，抑制选定的黑色素瘤细胞系，其敏感性比其他细胞系高三个数量级。这表明了一种潜在的新的作用模式和起点，开发Palmerolide作为治疗黑色素瘤癌症的先导。我们的合成研究将首次对这种独特的抗癌天然产物进行综合化学生物学评价。与公众健康相关：大多数获得FDA批准或正在进行高级临床研究的抗癌药物都是基于天然产品主导的。我们的研究将深入研究具有抗癌活性的新型天然产物。我们将开发这些天然产物和合成类似物的有效合成，以确定用于治疗人类肿瘤的抗癌先导化合物。

DESCRIPTION (provided by applicant): 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.