New Methods for the Synthesis of Unusual Peptides

合成特殊肽的新方法

基本信息

批准号：
7390857
负责人：
STEVEN L CASTLE
金额：
$ 21.33万
依托单位：
BRIGHAM YOUNG UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7390857
关键词：
3-hydroxybutanal Acidity Acids Alkylation Amides Amination Amino Acids Anti-Inflammatory Agents Anti-inflammatory Antifungal Agents Antimitotic Agents Antiparasitic Agents Architecture Area Arginine Biological Assay Biological Factors Chemistry Cinchona Alkaloids Classification Complex Copper Coupling Cyclic Peptides Cyclization Development Esters Evaluation Facility Construction Funding Category Generations Goals Hand Health Histidine Human Imidazole Indoles Intention Lead Left Leucine Link Mediating Methods Modeling Modification Molecular Object Attachment Palladium Peptide Synthesis Peptides Phase Physical condensation Preparation Process Protons Range Reaction Reliance Research Research Personnel Route Side Solid Solutions Staging Structure System Techniques Testing Tryptophan Tubulin Work amino group analog base catalyst celogentin A celogentin C cooking crosslink design epimerization improved indole interest novel nucleophilic addition polymerization programs racemization

项目摘要

DESCRIPTION (provided by applicant): The broad goal of this program is to develop new, effective synthetic methods for the synthesis of bioactive peptide natural products with unique structural features. The target that we have chosen as a vehicle for establishing this program is Celogentin C, a bicyclic octapeptide which is a potent antimitotic agent by virtue of its inhibition of the polymerization of tubulin. The unusual molecular architecture of Celogentin C includes a tryptophan residue with substitution at C-2 and C-6 of the indole side chain, a biaryl-type system characterized by the C-N bond between the indole and imidazole moieties, and a beta-substituted amino acid that results from the cross-link between the tryptophan and leucine side chains. We propose three novel synthetic methods for the construction of these interesting structures. The substituted central tryptophan will be prepared via incorporation of phase-transfer-catalyzed asymmetric alkylation chemistry into the Cook tryptophan synthesis. This work will also lead to the development of novel Cinchona alkaloid derived phase- transfer catalysts for both alkylations and aldol reactions. The latter process will afford beta-hydroxy amino acids. The indole-imidazole linkage will be formed by means of a copper- or palladium-catalyzed aryl amination reaction. Our intention is to perform this reaction in an intramolecular fashion in order to develop alternatives to macrolactamization for the cyclization of peptides. Finally, the beta-substituted amino acid system will be constructed via the chiral Lewis acid promoted conjugate addition of nucleophilic radicals to unsaturated nitro esters or amides. These substrates have great potential as intermediates in the preparation of amino acids. However, they have not been utilized in synthesis, likely due to concerns about the acidity of the resulting alpha-proton. After we have fully developed our new methods with model substrates, we will apply them to the total synthesis of Celogentin C. In addition to these methods, areas we will explore in the total synthesis include arginine protecting groups and the intramolecular Knoevenagel condensation. The synthesis is designed in a manner that will allow easy preparation of novel analogues for structure-activity studies. Thus, by generating compounds with potential medicinal value and facilitating the invention of synthetic methods applicable to a wide range of bioactive peptides, this program will have a profound effect on human health.

描述（由申请人提供）：该项目的总体目标是开发新的、有效的合成方法来合成具有独特结构特征的生物活性肽天然产物。我们选择作为建立该程序的载体的靶点是 Celogentin C，一种双环八肽，由于其抑制微管蛋白聚合而成为有效的抗有丝分裂剂。 Celogentin C 的独特分子结构包括在吲哚侧链的 C-2 和 C-6 处取代的色氨酸残基、以吲哚和咪唑部分之间的 C-N 键为特征的联芳基型系统以及 β 取代的氨基由色氨酸和亮氨酸侧链之间的交联产生的酸。我们提出了三种新颖的合成方法来构建这些有趣的结构。取代的中心色氨酸将通过将相转移催化的不对称烷基化化学结合到库克色氨酸合成中来制备。这项工作还将导致开发用于烷基化和羟醛反应的新型金鸡纳生物碱衍生的相转移催化剂。后一个过程将提供β-羟基氨基酸。吲哚-咪唑键将通过铜或钯催化的芳基胺化反应形成。我们的目的是以分子内方式进行该反应，以开发用于肽环化的大环内酰胺化的替代方案。最后，通过手性路易斯酸促进亲核基团与不饱和硝基酯或酰胺的共轭加成，构建β-取代的氨基酸系统。这些底物作为氨基酸制备的中间体具有巨大的潜力。然而，它们尚未用于合成，可能是由于担心所得α-质子的酸性。当我们用模型底物充分开发出我们的新方法后，我们将把它们应用到 Celogentin C 的全合成中。除了这些方法之外，我们在全合成中将探索的领域包括精氨酸保护基团和分子内 Knoevenagel 缩合。该合成的设计方式使得可以轻松制备用于结构活性研究的新型类似物。因此，通过产生具有潜在药用价值的化合物并促进适用于多种生物活性肽的合成方法的发明，该计划将对人类健康产生深远的影响。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synthesis of the celogentin C right-hand ring.

celogentin C 右环的合成。

DOI：
10.1021/ol060016f
发表时间：
2006-02-24
期刊：
Organic letters
影响因子：
5.2
作者：
Liwen He;Liping Yang;S. Castle
通讯作者：
S. Castle

Novel Cinchona alkaloid derived ammonium salts as catalysts for the asymmetric synthesis of beta-hydroxy alpha-amino acids via aldol reactions.

新型金鸡纳生物碱衍生的铵盐作为催化剂，通过羟醛反应不对称合成 β-羟基 α-氨基酸。

DOI：
发表时间：
2007-03-19
期刊：
影响因子：
1.8
作者：
Ma, Bing;Parkinson, Jared L;Castle, Steven L
通讯作者：
Castle, Steven L

Second-generation DBFOX ligands for the synthesis of beta-substituted alpha-amino acids via enantioselective radical conjugate additions.

第二代 DBFOX 配体，用于通过对映选择性自由基共轭加成合成 β 取代的 α-氨基酸。

DOI：
发表时间：
2008-11-21
期刊：
影响因子：
0
作者：
Banerjee, Biplab;Capps, Steven G;Kang, Junghoon;Robinson, Joshua W;Castle, Steven L
通讯作者：
Castle, Steven L

Stereoselective additions of thiyl radicals to terminal ynamides.

硫基自由基立体选择性加成到末端炔酰胺上。

DOI：
10.1021/ol1008679
发表时间：
2010-06-04
期刊：
Organic letters
影响因子：
5.2
作者：
Banerjee, Biplab;Litvinov, Dmitry N.;Kang, Junghoon;Bettale, Jennifer D.;Castle, Steven L.
通讯作者：
Castle, Steven L.

Synthesis of the acutumine spirocycle via a radical-polar crossover reaction.

通过自由基-极性交叉反应合成尖胺螺环。