Asymmetric Synthesis of Antitumor Natural Products

抗肿瘤天然产物的不对称合成

• 批准号: 8067982
• 负责人: JOHN A PORCO
• 金额: $ 32.71万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067982
• 关键词: Ally; Antitumor Natural Products; Biological; Biological Assay; Biological Factors; Biology; Boston; Cell Line; Chemicals; Chromones; Collaborations; Complex; DNA; Development; Dimerization; Discipline; Esters; Genomics; Goals; Health; Health Planning; Human; Hydrazones; Individual; Laboratories; Macrolides; Malignant Neoplasms; Medicine; Methodology; Methods; Modeling; National Cancer Institute; Organic Synthesis; Pathology; Play; Principal Investigator; Property; Public Health; Reaction; Research; Research Personnel; Scheme; Series; United States National Institutes of Health; Universities; Xanthones; antitumor agent; chemical reaction; chemical synthesis; dimer; drug discovery; interest; lobatamide C; lomaiviticin B; novel; programs; salicylate; silvestrol; tool

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.

描述（由申请人提供）：拟议的研究计划反映了主要研究者John A.小波尔科和他的小组在新的化学反应的发展和生物相关分子的合成使用有效的方法。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、epidithiidiketopiperazine（ETP）天然产物和最近分离的kibdelones，这三类具有抗肿瘤活性的复杂天然产物。他们将应用开发的方法学来化学合成复杂的目标，包括FL-120 B '，洛麦替星B，和ambewelamides/scabrosin酯，和kibdelone 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中心（NCGC）和国家癌症研究所（NCI）的研究人员的合作研究中，Porco及其同事将分析本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。本课题的主要目的是：研究重氮苯并芴类化合物FL-120 B '和洛麦维他星B'的不对称合成方法，并对合成化合物的DNA切割性能进行评价。完成了环二硫二酮哌嗪（ETP）天然产物vertihemiptellide A、龙涎香酰胺类化合物和rostratin A的合成。完成了多环口山酮类抗肿瘤药物基布地酮A、B和C的不对称合成和绝对构型归属。公共卫生相关性：有机合成是一门重要的学科，它在药物发现以及医学和生物学的相关领域中继续发挥关键作用。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物（包括抗肿瘤天然产物）的可行方法。复杂天然产物的计划不对称合成与公共健康的相关性需要鉴定新的具有生物活性的抗肿瘤剂。这些试剂应该可用作新的药理学工具和与各种病理学（包括各种人类癌症）相关的药物发现。