Chemistry and Biology of Antitumor Natural Products

抗肿瘤天然产物的化学和生物学

• 批准号: 7568766
• 负责人: JEF KAREL DE BRABANDER
• 金额: $ 25.25万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568766
• 关键词: Antarctic; Antineoplastic Agents; Antitumor Natural Products; Aquaculture; Architecture; Area; Belief; Biochemistry; Biological; Biological Factors; Biological Process; Biology; Cancer Biology; Cancer cell line; Cell Line; Chemicals; Chemistry; Chimera organism; Clinical Research; Complex; Development; Environment; Evaluation; FDA approved; Family; Foundations; Future; Goals; Growth; Human; Investigation; Laboratories; Lead; Malignant Neoplasms; Marines; Melanoma Cell; Methodology; Molecular; Pattern; Pharmacology; Porifera; Property; Protein Synthesis Inhibition; Protein Synthesis Inhibitors; Public Health; Reagent; Relative (related person); Reporting; Research; Research Design; Solid; Solutions; Structure; Structure-Activity Relationship; Synthesis Chemistry; Tumor Cell Line; Urochordata; analog; anticancer activity; base; cancer therapy; cytotoxicity; drug candidate; flexibility; in vivo; innovation; insight; interest; melanoma; novel; pederin; pre-clinical; preclinical evaluation; preclinical study; programs; research clinical testing; sound; tumor

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.

我们的研究计划的广泛目标是研究结构独特的化学和生物学 天然产物显示出有希望的针对实体人类肿瘤细胞系的差异细胞毒性， 提供与癌症生物学和潜在先导化合物相关的新见解，用于临床前评价 对抗人体实体肿瘤这个更新的应用程序特别侧重于小说的合成 天然产物Psymberin/Irciniastatin和Palmerglutamine。Psymberin/Irciniastatin为相关代谢物 从海绵中分离出来据报道，它们能有效地抑制人实体肿瘤细胞的生长 线在结构上，它们与pederin/mycalamide家族的蛋白质合成抑制剂有关，但与pederin/mycalamide家族的蛋白质合成抑制剂不同， 后者，Psymberin在癌细胞系中显示出前所未有的差异细胞毒性。我们提出了一个 Psymberin/Irciniastatin、其类似物和用于作用模式研究的探针试剂的全合成。 我们还将开发新的化学方法来制备Mycalamide-like化合物，以与 Psymberin为了充分剖析蛋白质合成抑制和分化的结构决定因素， 细胞毒这些研究将为先导化合物的鉴定和临床前研究提供坚实的基础。 人类癌症治疗领域，并提供适用于其他生物学相关的化学方法 抗癌天然产物。此外，我们还提出了一个新的高度收敛和适应性的总 从南极被囊动物中分离化合物棕榈酸酯的合成。帕默斯顿展示了一种独特的 在NCI的60细胞系组的人肿瘤中的差异细胞毒性特征，抑制选定的黑色素瘤 相对于其他细胞系具有三个数量级更高的灵敏度的细胞系。这表明 潜在的新的作用方式和起点的发展Palmercury作为一个领先的 黑色素瘤的治疗我们的合成研究将提供第一个进入一个综合化学品 对这种独特的抗癌天然产物进行生物学评价。 与公共卫生的相关性：大多数抗癌药物已获得FDA批准或处于高级临床阶段 研究是基于天然产品铅。我们的研究将彻底调查新的天然产品 具有抗癌活性。我们将开发这些天然产物和合成类似物的有效合成方法 以鉴定用于治疗人类肿瘤癌症的抗癌先导物。