Synthetic/Mechanistic Investigations of Antitumor Agents

抗肿瘤药物的合成/机理研究

• 批准号: 7266078
• 负责人: GARY ALLEN SULIKOWSKI
• 金额: $ 27.9万
• 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/7266078
• 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）：本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，以推进复杂分子合成和药物发现领域。这些目标将需要一种跨学科的方法来定义这些天然产物使用化学生物学工具选择性靶向癌细胞的机制基础，主要依赖于化学合成的力量。因此，我们实验室的贡献将集中在开发高效和立体控制的策略，用于合成复杂的天然产物及其各自感兴趣的同类物。合作的努力将使我们能够开发SAR配置文件，最终将导致识别的细胞目标的次级代谢产物，我们打算研究。即将到来的资助期的具体目标包括：（1）化学合成叠氮基甲萘醌;（2）与Brian Bachmann教授合作，使用前体定向生物合成开发非天然糖苷配基的酶促糖基化程序（范德比尔特化学生物学研究所）;（3）杀氨菌素的立体控制合成，杀氨菌素是一种聚酮衍生的天然产物，其选择性地诱导ras依赖性细胞的凋亡;（4）与Dan Liebler教授和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，鉴定异甘草定和hibarimicin E的细胞靶标;（5）hibarimicinone和hibarimicin分流代谢物HMP-Y1的化学合成。外行语言描述：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物化学工具在分子水平上了解这些化合物如何靶向癌细胞。这一领域的进展可能对癌症的治疗产生重大影响。