Synthetic/Mechanistic Investigations of Antitumor Agents

抗肿瘤药物的合成/机理研究

• 批准号: 7623190
• 负责人: GARY ALLEN SULIKOWSKI
• 金额: $ 29.12万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623190
• 关键词: Address; Anabolism; Apoptosis; Area; Biochemical; Biological; Biological Factors; Biology; Biotin; Cell Differentiation process; Cells; Chemicals; Collaborations; Complex; Deoxy Sugars; Development; Evaluation; Genes; Genotype; Goals; Grant; HL-60 Cells; Institutes; Investigation; Japan; Label; Laboratories; Language; Lead; Ligation; Macrolides; Malignant Neoplasms; Methods; Molecular; Normal Cell; Oncogenes; Oncogenic; Pattern; Procedures; Production; Proteomics; Reporting; Research; Research Personnel; Shunt Device; Signal Transduction; Soil; Structure; Time; Transformed Cell Line; Work; ammocidin; anticancer research; antitumor agent; apoptolidin; base; cancer cell; cancer therapy; cellular targeting; chemical synthesis; cytotoxic; cytotoxicity; drug discovery; glycosylation; hibarimicinone; interdisciplinary approach; interest; microorganism; neoplastic cell; professor; programs; scaffold; src-Family Kinases; sugar; tool; tumor

DESCRIPTION (provided by applicant): The long term objective of this research program is to use cell-specific cytotoxic natural products as vehicles to advance the fields of complex molecule synthesis and drug discovery. These goals will require an interdisciplinary approach to define the mechanistic basis by which these natural products selectively target cancer cells using the tools of chemical biology, relying primarily upon the power of chemical synthesis. As such, contributions from our laboratory will focus on the development of efficient and stereocontrolled strategies for the synthesis of complex natural products and their respective congeners of interest. Collaborative efforts will allow us to develop SAR profiles that will ultimately lead to identification of the cellular target for the secondary metabolites that we intend to study. Specific Aims for the forthcoming grant period include: (1) Chemical synthesis azido apoptolidinone; (2) Development of procedures for the enzymatic glycosylation of the unnatural aglycones using precursor directed biosynthesis in collaboration with Professor Brian Bachmann (Vanderbilt Institute of Chemical Biology); (3) Stereocontrolled synthesis of ammocidin, a polyketide derived natural product that selectively induces apoptosis in ras-dependent cells; (4) Identification of the cellular target(s) of apoptolidin and hibarimicin E using a chemical proteomics strategy in collaboration with Professors Dan Liebler and Larry Marnett (Vanderbilt Institute of Chemical Biology); (5) Chemical synthesis of hibarimicinone and the hibarimicin shunt metabolite HMP-Y1. Lay language description: One long term objective is to develop methods for the assembly of a group of natural products that have proven to selectively eliminate cancer cells without harming normal cells. A second objective is to use various chemical and biochemical tools to understand, at a molecular level, how these compounds target cancer cells. Advances in this area could have significant impact in the treatment of cancer.

描述（由申请人提供）：该研究计划的长期目标是使用细胞特异性细胞毒性天然产物作为载体来推进复杂分子合成和药物发现领域。这些目标需要采用跨学科的方法来定义这些天然产物使用化学生物学工具（主要依靠化学合成的力量）选择性靶向癌细胞的机制基础。因此，我们实验室的贡献将集中于开发有效和立体控制的策略来合成复杂的天然产物及其各自感兴趣的同系物。通过共同努力，我们将能够开发 SAR 谱，最终确定我们打算研究的次级代谢物的细胞靶标。即将到来的资助期的具体目标包括： (1) 化学合成叠氮基凋亡烷酮； (2) 与 Brian Bachmann 教授（范德比尔特化学生物学研究所）合作，开发利用前体定向生物合成对非天然苷元进行酶促糖基化的程序； （3）阿莫西丁的立体控制合成，阿莫西丁是一种聚酮化合物衍生的天然产物，可选择性诱导ras依赖性细胞凋亡； (4) 与 Dan Liebler 和 Larry Marnett 教授（范德比尔特化学生物学研究所）合作，使用化学蛋白质组学策略鉴定凋亡素和 hibarimicin E 的细胞靶标； (5) 喜巴米星及其分流代谢物HMP-Y1的化学合成。通俗语言描述：一个长期目标是开发一组天然产物的组装方法，这些天然产物已被证明可以选择性地消除癌细胞而不伤害正常细胞。第二个目标是使用各种化学和生化工具在分子水平上了解这些化合物如何靶向癌细胞。该领域的进展可能对癌症治疗产生重大影响。