Asymmetric Synthesis of Antitumor Natural Products

描述（由申请人提供）：提议的研究计划反映了首席研究员John A. Porco, Jr.和他的团队对新化学反应开发和使用有效方法合成生物相关分子的兴趣。他们的总体目标是开发和完善新的合成方法，用于不对称合成重氮苯并芴天然产物、附睾二酮哌嗪（ETP）天然产物和最近分离的基德龙，这三类具有抗肿瘤活性的复杂天然产物。他们将把开发的方法应用于复杂靶标的化学合成，包括FL-120B'、洛麦维菌素B、安贝贝酰胺/松香酯和基苯德龙A、B和c。在与波士顿大学、美国国立卫生研究院化学基因组学中心（NCGC）和美国国家癌症研究所（NCI）的研究人员的合作研究中，Porco和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。他们的提案被组织成三个核心项目，反映了他们在新反应方法开发、机理研究和生物活性分子合成应用方面的基本兴趣。该项目的目的是：开发一种有效的不对称合成重偶氮苯并氟芴FL-120B'和洛马维菌素B，并评价合成化合物的DNA切割特性。完成epidithiodiketopiperazine （ETP）天然产物vertihemiptellide A、ambewelamide /scabrosin酯和rostratin A的合成。完成多环山酮类抗肿瘤药物kibdelones 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，在药物发现和医学和生物学相关领域继续发挥关键作用。作为我们实验室对新化学反应方法的兴趣的一部分，我们继续开发生物活性天然产品的可行方法，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共卫生的相关性需要鉴定新的、具有生物活性的抗肿瘤剂。这类药物可以作为新的药理学工具，用于各种病理（包括各种人类癌症）的药物发现。

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.