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.

项目总结/摘要 复杂天然产物的化学和生物学的详细研究， 水平提供了关键的洞察力，以了解他们的行动模式，并使发展 治疗各种人类疾病的新方法。该研究计划重点 开发高效简洁的结构复杂的全化学合成方法， 和生物活性的天然产品，通过系统的发现，开发， 应用新的合成策略和方法。目标的选择基于 分子结构的新奇，先前合成研究的缺乏， 为制定新的战略和方法，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 感兴趣的是环色胺的定向、区域选择性、立体选择性和有效结合 提供后期耦合的子结构，以确保具有挑战性的联系，包括 在四级立体中心完全立体控制。会聚和引导组装 高级片段通过应用新的高选择性转化来补充 快速生成复杂的分子。这些包括立体保留 二酮哌嗪羟基化，然后立体控制硫化，采用各种 在此程序中开发的新试剂和条件，可以访问相应的 表聚硫代二酮哌嗪。有了这个项目， 复杂的生物碱和衍生物，我们寻找机会进行广泛的比较分析， 化合物的组，以获得有关结构活性关系的有价值的见解， 可以告知设计的衍生物的合成，以促进进一步的生物化学合作 调查事务所该计划将继续提供稀有和珍贵的合成样品， 化合物的结构验证和详细的化学和生物学检查。 这种丰富的生物碱家族的公认生物活性确保了许多生物活性。 通过这些努力获得的相关中间体和衍生物也将获得巨大的 作为机械工具和新的生物活性化合物，因此它们将是 通过我们的多学科和合作参与进行持续评估。

项目成果

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

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

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