Chemical Synthesis of Complex Natural Products for Translational Science

用于转化科学的复杂天然产物的化学合成

• 批准号: 9920757
• 负责人: JOHN A PORCO
• 金额: $ 66.79万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920757
• 关键词: Address; Antibiotics; Antineoplastic Agents; Biological; Biomimetics; Catalysis; Chromones; Clinical; Clinical Research; Collaborations; Complex; Copper; Development; Dimerization; Flavonoids; Funding; Goals; Grant; Human; Malignant Neoplasms; Manuscripts; Mediating; Methodology; Methods; National Institute of General Medical Sciences; Natural Products; Organic Chemistry; Pharmacology; Principal Investigator; Property; Public Health; Publications; Quinones; Research; Research Personnel; Translational Research; Tubulin; Viral; Work; Xanthones; antineoplastic antibiotics; antitumor agent; bioactive natural products; chemical synthesis; dimer; flexibility; inhibitor/antagonist; innovation; novel; professor; programs; public health relevance

 DESCRIPTION (provided by applicant): The goals of the proposed MIRA (R35) research program are to continue chemical syntheses of bioactive molecules and expand our efforts and capabilities in translational science. The MIRA effort will allow flexibility and stability to enabe important new research directions that come up during the course of research. Our two NIGMS-funded RO1 grants (Biomimetic Synthesis of Complex Natural Products (GM-073855) and Chemical Synthesis of Bioactive Flavonoid and Xanthone-Derived Natural Products) have been highly productive and have led to 41 publications from 2015 - 2010. These include 19 collaborative manuscripts with clinical and biological investigators. As part of our studies, we have taken opportunities to address key questions and contemporary needs in organic chemistry including asymmetric catalysis of photocycloadditions, enantioselective dearomatization, and atropselective synthesis. Key accomplishments in the past five years include asymmetric photocycloadditions of 3-hydroxyflavones to access rocaglate antitumor agents, synthesis of derivatives of the tubulin inhibitor chamaecypanone C using copper-mediated enantioselective oxidative dearomatization, synthesis of the anticancer agents and antibiotics kibdelones A and C using Pt(IV)-mediated arylations of quinone monoketals, and synthesis of the antibiotic rugulotrosin A employing vinylogous addition of siloxyfurans to chromones and atropselective dimerization. As part of the proposed MIRA project, the Principal Investigator Professor John Porco and colleagues will continue development of novel synthetic methodologies for concise entry to bioactive classes of natural products including oxaphenalenones, meroterpenoids, polyprenylated acylphloroglucinols, tetrahydroxanthones, and dimeric chromones. The project will continue major emphasis on collaborations to study biological properties and mode of action (MoA) of target molecules for ultimate use as pharmacological therapies for human cancers as well as viral and bacterial illnesses. It is anticipated that the MIRA effort will allow us to continue development of innovative syntheses of complex natural products and derivatives and continue work to highly interface these studies with applications of compounds in clinical and translational research.

 描述（由申请人提供）：拟议的MIRA（R35）研究计划的目标是继续生物活性分子的化学合成，并扩大我们在转化科学方面的努力和能力。MIRA的努力将允许灵活性和稳定性，以实现研究过程中出现的重要新研究方向。我们的两个NIGMS资助的RO 1赠款（复杂天然产物的仿生合成（GM-073855）和生物活性黄酮和氧杂蒽酮衍生的天然产物的化学合成）具有很高的生产力，并导致41出版物从2015 - 2010。其中包括19篇与临床和生物学研究者合作的手稿。作为我们研究的一部分，我们抓住机会解决有机化学中的关键问题和当代需求，包括光环加成的不对称催化，对映选择性脱芳构化和atropselective合成。过去五年的主要成就包括3-羟基黄酮的不对称光环合反应以获得罗卡酸抗肿瘤药物、使用铜介导的对映选择性氧化脱芳构化合成微管蛋白抑制剂chamaecypanone C的衍生物、合成抗癌药物和抗生素基布酮A和C使用Pt（IV）介导的醌单缩酮芳化反应，以及采用异呋喃与色酮的乙烯基加成和阻转选择性二聚来合成抗生素rugulotrosin A。作为拟议的MIRA项目的一部分，首席研究员John Porco教授及其同事将继续开发新的合成方法，用于简明地进入天然产物的生物活性类别，包括oxaphenalenones，meroterpenoids，polyprenylated acylphloroglucinols，tetrahydroxanthones和二聚色酮。该项目将继续主要侧重于合作研究靶分子的生物学特性和作用模式（MoA），最终用作人类癌症以及病毒和细菌疾病的药理学治疗。预计MIRA的努力将使我们能够继续开发复杂天然产物和衍生物的创新合成，并继续努力将这些研究与化合物在临床和转化研究中的应用高度对接。