Chemistry and Biology of Antitumor Natural Products

描述（由申请人提供）：我们的研究计划的主要目标是研究结构独特的天然产物的化学和生物学，这些产物对实体人肿瘤细胞系显示出有希望的差异细胞毒性，最终提供与癌症生物学相关的新见解和潜在的先导化合物，用于实体人肿瘤的临床前评估。本更新申请特别关注新的天然产物Psymberin / Irciniastatin和Palmerolide的合成。Psymberin / ircinastatin是从海绵中分离出来的相关代谢物。据报道，它们能有效抑制实体人肿瘤细胞系的生长。从结构上看，它们与pederin / mycalamide家族的蛋白质合成抑制剂有关，但与后者不同的是，psymberin在癌细胞系中表现出前所未有的细胞毒性差异。我们提出了一种全合成的Psymberin / ircinastatin，其类似物和探针试剂的作用方式研究。我们还将开发新的化学方法来制备mycalamide类化合物，以便与Psymberin进行直接比较，从而全面剖析蛋白质合成抑制和差异细胞毒性的结构决定因素。这些研究将为人类癌症治疗领域的铅鉴定和临床前研究提供坚实的基础，并为其他生物学相关的抗癌天然产物提供化学方法。此外，我们还提出了一种新的高收敛性和适应性的Palmerolide全合成方法，Palmerolide是从南极被囊动物中分离出来的化合物。Palmerolide在NCI的60个人类肿瘤细胞系中显示出独特的细胞毒性差异，抑制选定的黑色素瘤细胞系，其敏感性比其他细胞系高3个数量级。这表明了一种潜在的新的作用模式和起点，Palmerolide发展为黑色素瘤癌症治疗的先导。我们的合成研究将首次提供对这种独特的抗癌天然产物进行综合化学生物学评估的入口。与公众健康相关：大多数FDA批准的抗癌药物或处于高级临床研究阶段的抗癌药物都是基于天然产品先导物。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，以确定治疗人类肿瘤癌症的抗癌线索。

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.