Synthetic/Mechanistic Investigations of Antitumor Agents

描述（由申请人提供）：本研究项目的长期目标是利用细胞特异性细胞毒性天然产物作为载体，推进复杂分子合成和药物发现领域的发展。这些目标将需要一种跨学科的方法来定义这些天然产物选择性靶向癌细胞的机制基础，利用化学生物学的工具，主要依靠化学合成的力量。因此，我们实验室的贡献将集中在复杂天然产物及其各自感兴趣的同源物的合成的高效和立体控制策略的发展上。合作努力将使我们能够开发SAR谱，最终确定我们打算研究的次级代谢物的细胞靶标。下一资助期的具体目标包括：(1)化学合成叠氮酮apoptolidinone；(2)与Brian Bachmann教授（Vanderbilt化学生物学研究所）合作，开发利用前体定向生物合成的非天然苷元的酶促糖基化程序；(3)立体控制合成氨莫西丁，一种选择性诱导ras依赖性细胞凋亡的聚酮衍生天然产物；(4)与范德比尔特化学生物学研究所的Dan Liebler和Larry Marnett教授合作，利用化学蛋白质组学策略鉴定apoptolidin和hibarimicin E的细胞靶点；(5) hibarimicinone及hibarimicin分流代谢产物HMP-Y1的化学合成。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。这一领域的进展可能对癌症的治疗产生重大影响。

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.