Synthesis and Study of Cyclotryptamine and Diketopiperazine Alkaloids

环色胺和二酮哌嗪生物碱的合成与研究

• 批准号: 10059252
• 负责人: Mohammad Movassaghi
• 金额: $ 44.95万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059252
• 关键词: Alkaloids; Antibiotics; Architecture; Biochemical; Biological; Biology; Biomimetics; Chemicals; Chemistry; Childhood Malignant Brain Tumor; Complement; Complex; Coupling; Cyclodepsipeptides; Development; Diffuse intrinsic pontine glioma; Dimerization; Ensure; Evaluation; Family; Future; Generations; Glioblastoma; Grant; Hela Cells; Human; Hydroxylation; Investigation; Membrane; Methodology; Molecular; Molecular Probes; Natural Products; Peptide Synthesis; Phase; Play; Preparation; Reagent; Research; Research Activity; Role; Sampling; Secure; Silver; Solid; Structure; Structure-Activity Relationship; Sulfides; Therapeutic; Tryptamines; Tryptophan; Validation; analog; anti-cancer; base; chemical synthesis; chetomin; comparative; design; diazene; diketopiperazine; disulfide bond; insight; interdisciplinary collaboration; interest; multidisciplinary; novel; novel strategies; programs; self assembly; tool

Project Summary/Abstract The detailed study of the chemistry and biology of complex natural products at a fundamental level provides critical insight to understanding their mode of action and enables development of new approaches for treatment of various human ailments. This research program focuses on the development of efficient and concise total chemical syntheses of structurally complex and biologically active natural products through the systematic discovery, development, and application of new synthetic strategies and methodologies. The targets are selected based on novelty of molecular architecture, paucity of prior synthetic studies, abundance of opportunities for development of new strategies and methodologies, possession of significant biological activity, and the potential for future chemical and biological studies. This program will focus on synthetic studies of the rich family of cyclotryptamine and diketopiperazine alkaloids. Of central interest is the directed, regioselective, stereoselective, and efficient union of cyclotryptamine substructures providing late-stage couplings to secure challenging linkages, including complete stereocontrol at quaternary stereogenic centers. Convergent and guided assembly of advanced fragments is complemented by application of new highly selective transformations for the rapid generation of molecular complexity. These include stereoretentive diketopiperazine hydroxylation followed by stereocontrolled sulfidation, employing a variety of new reagents and conditions developed in this program, to access the corresponding epipolythiodiketopiperazines. With this program's access to potently bioactive families of complex alkaloids and derivatives, we look for opportunities for extensive comparative analysis of groups of compounds to gain valuable insight concerning structure-activity relationships that can inform synthesis of designed derivatives to facilitate further biochemical collaborative investigations. This program will continue to provide synthetic samples of rare and precious compounds for structure validation and detailed examination of their chemistry and biology. The well recognized biological activity of this rich family of alkaloids ensure that the many related intermediates and derivatives accessed through these efforts will also behold great promise both as mechanistic tools and as new bioactive compounds, and thus they will be subject to continuous evaluation through our multidisciplinary and collaborative engagements.

项目概要/摘要 从根本上详细研究复杂天然产物的化学和生物学 水平提供了重要的见解来理解他们的行动模式并促进发展 治疗各种人类疾病的新方法。该研究计划重点 开发结构复杂的高效、简洁的全化学合成方法 通过系统的发现、开发和生产具有生物活性的天然产物 新合成策略和方法的应用。目标的选择基于 分子结构新颖，缺乏先前的合成研究，机会丰富 为了开发新的战略和方法，拥有重要的生物 活性以及未来化学和生物学研究的潜力。该计划将重点关注 丰富的环色胺和二酮哌嗪生物碱家族的合成研究。中央的 兴趣是环色胺的定向、区域选择性、立体选择性和有效结合 子结构提供后期耦合以确保具有挑战性的连接，包括 在四元立体中心完成立体控制。收敛和引导组装 先进的片段通过新的高选择性转化的应用得到补充 用于快速生成分子复杂性。这些包括立体保持 二酮哌嗪羟基化，然后立体控制硫化，采用多种方法 本计划中开发的新试剂和条件，以获得相应的 环氧二酮哌嗪类。通过该计划可以获得有效的生物活性家族 复杂的生物碱和衍生物，我们寻找进行广泛比较分析的机会 化合物组以获得有关结构-活性关系的宝贵见解 可以为设计衍生物的合成提供信息，以促进进一步的生化协作 调查。该计划将继续提供稀有珍贵的合成样品 用于结构验证和化学和生物学详细检查的化合物。 这一丰富的生物碱家族公认的生物活性确保了许多 通过这些努力获得的相关中间体和衍生物也将得到巨大的发展 有望作为机械工具和新的生物活性化合物，因此它们将 通过我们的多学科和协作活动进行持续评估。

项目成果

Quantitative Modeling of Bis(pyridine)silver(I) Permanganate Oxidation of Hydantoin Derivatives: Guidelines for Predicting the Site of Oxidation in Complex Substrates.

• DOI: 10.1021/jacs.7b09541
• 发表时间: 2017-11-01
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Bischoff AJ;Nelson BM;Niemeyer ZL;Sigman MS;Movassaghi M
• 通讯作者: Movassaghi M

Concise Total Synthesis of (+)-Gliocladins B and C.

• DOI: 10.1039/c2sc20270k
• 发表时间: 2012-01-01
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Boyer N;Movassaghi M
• 通讯作者: Movassaghi M

Radical-mediated dimerization and oxidation reactions for the synthesis of complex alkaloids.

自由基介导的二聚化和氧化反应，用于合成复杂的生物碱。

• DOI: 10.2533/chimia.2012.389
• 发表时间: 2012
• 期刊: Chimia
• 影响因子: 1.2
• 作者: Lathrop SP;Kim J;Movassaghi M
• 通讯作者: Movassaghi M

Total synthesis of himastatin.

• DOI: 10.1126/science.abm6509
• 发表时间: 2022-02-25
• 期刊: SCIENCE
• 影响因子: 56.9
• 作者: D'Angelo, Kyan A.;Schissel, Carly K.;Pentelute, Bradley L.;Movassaghi, Mohammad
• 通讯作者: Movassaghi, Mohammad

Structure and Function of NzeB, a Versatile C-C and C-N Bond-Forming Diketopiperazine Dimerase.

• DOI: 10.1021/jacs.0c06312
• 发表时间: 2020-10-14
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Shende VV;Khatri Y;Newmister SA;Sanders JN;Lindovska P;Yu F;Doyon TJ;Kim J;Houk KN;Movassaghi M;Sherman DH
• 通讯作者: Sherman DH