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.

项目摘要/摘要 对复杂的天然产物的化学和生物学的详细研究 级别为理解他们的行动模式提供关键洞察力，并使发展成为可能 治疗各种人类疾病的新方法。这项研究计划的重点是 高效简明的结构络合物全化学合成研究进展 和生物活性天然产物通过系统的发现，开发和 应用新的综合战略和方法。目标是根据以下条件选择的 分子结构的新颖性，先前合成研究的匮乏，机会的丰富 用于开发新的战略和方法，拥有重要的生物学 活性，以及未来化学和生物学研究的潜力。本节目将重点关注 富含环色胺和二酮基哌嗪生物碱家族的合成研究。属于中环 人们感兴趣的是环色胺的定向、区域选择性、立体选择性和高效结合。 提供后期联结以确保具有挑战性的联系的基础结构，包括 在第四纪立体发生中心进行完全立体控制。汇聚的和导向的组件 先进的片段通过应用新的高选择性转换来补充 因为分子复杂性的快速产生。其中包括立体保持器 二酮基哌嗪羟化，然后立体控制硫化，使用了各种 在本计划中开发的新试剂和条件，以获取相应的 表多硫代二酮并哌嗪。随着这个项目能够接触到具有潜在生物活性的家庭 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 以获得关于结构-活性关系的有价值的见解 可以通知设计的衍生物的合成，促进进一步的生物化学合作 调查。该计划将继续提供稀有和珍贵的合成样品 用于结构验证和详细检查其化学和生物学的化合物。 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品也将看到巨大的 作为机械工具和新的生物活性化合物的前景，因此它们将是 通过我们的多学科和协作活动进行持续评估。

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