Asymmetric Synthesis of Antitumor Natural Products

描述(由申请人提供)：建议的研究计划反映了首席研究员小约翰·A·波尔科和他的团队对新的化学反应开发和使用有效方法合成生物悬浮剂分子的兴趣。他们的总体目标是开发和改进新的合成方法，用于重氮苯并荧天然产物、表硫二酮基哌嗪(ETP)天然产物和最近分离的吉布地酮，这三类具有抗肿瘤活性的复杂天然产物的不对称合成。他们将把开发的方法学应用于复杂靶标的化学合成，包括FL-120B‘、洛麦维菌素B、Ambewell amamide/scabrosin酯，以及kibdelone A、B和C。在与波士顿大学、NIH化学基因组中心(NCGC)和国家癌症研究所(NCI)的研究人员合作的研究中，Porco及其同事将分析在研究过程中产生的天然和非天然化合物的生物活性。他们的建议被组织成三个核心项目，反映了他们对新反应方法开发、机理研究和生物活性分子合成应用的根本兴趣。该项目的目的是：开发一种高效的重氮苯并荧烯FL-120B‘和洛麦维菌素B的不对称合成方法，并评价合成化合物的DNA切割性能。完成表硫二酮并哌嗪(ETP)天然产物赤霉素A、安贝韦酰胺/赤霉素酯和罗司他丁A的合成。完成多环X-酮类抗肿瘤药物Kibdelone A、B和C的不对称合成和绝对构型分配。公共卫生相关性：有机合成是一门重要的学科，在药物开发以及医学和生物学的相关领域继续发挥关键作用。作为我们实验室对新的化学反应方法学的兴趣的一部分，我们继续开发具有生物活性的天然产品，包括抗肿瘤天然产品。计划中的复杂天然产物的不对称合成与公众健康的相关性需要鉴定新的、具有生物活性的抗肿瘤药物。这类药物应该作为新的药理学工具，并在与各种病理相关的药物发现中发挥作用，包括各种人类癌症。

DESCRIPTION (provided by applicant): The proposed research program reflects the interest of the Principal Investigator, John A. Porco, Jr., and his group in new chemical reaction development and the synthesis of biorelevant molecules using efficient approaches. Their overall goal is to develop and refine new synthetic methodologies for the asymmetric syntheses of diazobenzofluorene natural products, the epidithiidiketopiperazine (ETP) natural products, and the recently isolated kibdelones, three classes of complex natural products with demonstrated antitumor activity. They will apply the methodologies developed to the chemical synthesis of complex targets including FL-120B', lomaiviticin B, and the ambewelamides/scabrosin esters, and kibdelones A, B, and C. In collaborative studies with investigators at Boston University, the NIH Chemical Genomics Center (NCGC), and the National Cancer Institute (NCI), Porco and colleagues will assay the biological activity of natural and unnatural compounds produced during the course of this research. Their proposal is organized into three core projects reflecting their fundamental interest in new reaction methodology development, mechanistic studies, and applications towards the synthesis of biologically active molecules. The aims of the proposed project are: To develop an efficient asymmetric synthesis of the diazobenzofluorenes FL-120B' and lomaiviticin B and evaluate the DNA cleavage properties of synthetic compounds. To complete the syntheses of the epidithiodiketopiperazine (ETP) natural products vertihemiptellide A, the ambewelamides/scabrosin esters, and rostratin A. To complete the asymmetric syntheses and absolute configuration assignment of the polycyclic xanthone antitumor agents kibdelones A , B, and C. PUBLIC HEALTH RELEVANCE: Organic synthesis is an important discipline which continues to play a key role in drug discovery and in the allied fields of medicine and biology. As part of our laboratory's interest in new chemical reaction methodology, we continue to develop enabling approaches to bioactive natural products including antitumor natural products. The relevance to public health of the planned asymmetric syntheses of complex natural products entails identification of novel, biologically active antitumor agents. Such agents should be useful as novel pharmacological tools and in drug discovery related to various pathologies, including a variety of human cancers.