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

基本信息

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
项目类别：
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

项目摘要

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/摘要基本的复杂天然产品化学和生物学的详细研究级别为理解其行动方式提供了关键的见解，并使发展能够发展用于治疗各种人类疾病的新方法。该研究计划重点关于结构复杂的有效和简洁的总化学合成的发展以及通过系统的发现，开发和生物活跃的天然产品新的合成策略和方法的应用。基于分子结构的新颖性，先前合成研究的稀少，机会丰富为了制定新策略和方法论，拥有重要的生物学活动，以及未来化学和生物学研究的潜力。该程序将重点关注富含环丙胺和二酮替嗪生物碱的合成研究。中央兴趣是环丙胺的定向，区域选择性，立体选择性和有效的结合提供晚期耦合以确保具有挑战性的联系，包括在第四纪立体源性中心完全立体控制。收敛和指导组装高级片段是通过应用新的高度选择性转换来补充的为了快速产生分子复杂性。这些包括立体定论二甲苯吡嗪羟基化，然后是立体控制的硫化，采用多种该程序中开发的新试剂和条件，以访问相应的附生二邻苯吡嗪。随着该计划获得有效的生物活性家庭复杂的生物碱和衍生物，我们为广泛的比较分析寻找机会一组化合物，以获得有关结构活性关系的宝贵见解可以告知设计衍生物的综合，以促进进一步的生化协作调查。该程序将继续提供稀有和珍贵的合成样本结构验证和对其化学和生物学的详细检查的化合物。这个丰富的生物碱家族的众所周知的生物学活性确保了许多通过这些努力访问的相关中间体和衍生物也将很棒将作为机械工具和新的生物活性化合物承诺，因此它们将是通过我们的多学科和协作参与，可以持续评估。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

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

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

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