Synthesis of Anticancer Pyran Natural Products

抗癌吡喃天然产物的合成

• 批准号: 7655031
• 负责人: Karl A Scheidt
• 金额: $ 27.56万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-16 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7655031
• 关键词: Antitumor Natural Products; Architecture; Biological; Biological Factors; Breast; Chemicals; Collaborations; Comprehensive Cancer Center; Development; Evaluation; Family; Flavanones; Goals; Grant; Human; Investigation; Knowledge; Malignant Neoplasms; Malignant neoplasm of pancreas; Methodology; Molecular; Organic Synthesis; Oxygen; Property; Prostate; Pyrans; Reaction; Research; Research Personnel; Solutions; Structure; Tumor Cell Line; Universities; analog; antineoplastic antibiotics; butenolide; cancer prevention; chemotherapeutic agent; design; flavanone; interest; isosilybin; novel; novel therapeutics; programs; tool

Investigating the chemical reactivity and biological activity of anti-tumor natural products is vital to understanding their mechanism of action and developing new therapeutics for the treatment and/or prevention of cancer. This research program aims to develop efficient synthesis of biologically active natural products possessing six-membered oxygen heterocycles through the development and subsequent application of new tactics and methodologies for organic synthesis. Strategies that generate the targeted natural products structures while providing broad solutions to synthesizing related families of compounds will be pursued. The targets selected for these investigations possess interesting and novel molecular architecture, lack significant prior synthetic studies, and have promising biological activity in the context of cancer. The planned synthetic approaches are designed to feature catalytic stereoselective pyran-forming reactions, the enantioselective synthesis of flavanones, and incorporate multiple bond forming sequences. The specific goals of this research are: (1) Synthesis of the natural products chrolactomycin and okilactomycin. These antitumor antibiotics possess a unique and highly oxygenated tricyclic core. We will use a new butenolide macrocyclization/conjugate addition approach as the key strategic sequence. (2) Total synthesis of exiguolide (3) Syntheses of flavanone natural products abyssinone II and kurarinone. We will employ a new enantioselective flavanone synthesis catalyzed by chiral thioureas for the syntheses of these compounds. (4) Evaluate all compounds in these studies for their activity against various human tumor cell lines including breast, prostate, colon, and pancreatic cancer. This last aim will be accomplished in a collaboration combining our synthetic knowledge and capabilities acquired in Aims 1-3 with two expert cancer researchers at Northwestern’s Robert H. Lurie Comprehensive Cancer Center and one expert bioorganic chemist at Yale University

研究抗肿瘤天然产物的化学反应性和生物活性对于了解其作用机制和开发治疗和/或预防癌症的新疗法至关重要。该研究项目旨在通过有机合成新策略和方法的开发和后续应用，开发具有六元氧杂环的生物活性天然产物的高效合成。我们将寻求生成目标天然产物结构，同时为合成相关化合物家族提供广泛解决方案的策略。这些研究选择的靶标具有有趣且新颖的分子结构，缺乏重要的先前合成研究，并且在癌症背景下具有有前途的生物活性。计划的合成方法旨在以催化立体选择性吡喃形成反应、黄烷酮的对映选择性合成为特征，并结合多个成键序列。 本研究的具体目标是：（1）天然产物Chrolactomycin和Okilactomycin的合成。这些抗肿瘤抗生素具有独特的高氧三环核心。我们将使用新的丁烯酸内酯大环化/共轭加成方法作为关键的战略序列。 (2)exigigolide的全合成。 (3)黄烷酮天然产物abyssinone II和kurarinone的合成。我们将采用一种由手性硫脲催化的新型对映选择性黄烷酮合成方法来合成这些化合物。 (4) 评估这些研究中的所有化合物对各种人类肿瘤细胞系（包括乳腺癌、前列腺癌、结肠癌和胰腺癌）的活性。最后一个目标将通过将我们在目标 1-3 中获得的综合知识和能力与西北大学 Robert H. Lurie 综合癌症中心的两名专家癌症研究人员和耶鲁大学的一名专家生物有机化学家合作来实现