New Methods for the Synthesis of Unusual Peptides

合成特殊肽的新方法

• 批准号: 6871230
• 负责人: STEVEN L CASTLE
• 金额: $ 22.5万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6871230
• 关键词: alkylation; antimitotics; bicyclic compound; biological products; chemical addition; chemical bond; chemical substitution; cyclization; method development; peptide chemical synthesis; peptide structure; racemization; stereoisomer; tryptophan

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）：该计划的广泛目标是开发新的，有效的合成方法，用于合成具有独特结构特征的生物活性肽天然产物。我们选择Celogentin C作为建立该程序的载体，Celogentin C是一种双环八肽，由于其抑制微管蛋白的聚合而成为有效的抗有丝分裂剂。Celogentin C的不寻常分子结构包括在吲哚侧链的C-2和C-6处具有取代的色氨酸残基、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由色氨酸和亮氨酸侧链之间的交联产生的β-取代的氨基酸。我们提出了三种新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引入Cook色氨酸合成中来制备。这项工作也将导致开发新的金鸡纳生物碱衍生的相转移催化剂的烷基化和羟醛缩合反应。后一种方法将提供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。我们的目的是在分子内的方式进行这一反应，以开发替代大环内酰胺环化的肽。最后，通过手性刘易斯酸促进的亲核自由基与不饱和硝基酯或酰胺的共轭加成，构建β-取代氨基酸体系。这些底物在制备氨基酸的中间体中具有很大的潜力。然而，它们尚未用于合成，可能是由于对所得α-质子的酸性的担忧。在我们充分发展了我们的新方法与模型底物，我们将把它们应用到全合成Celogentin C。除了这些方法，我们将在全合成中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，将允许容易地制备新的类似物的结构-活性研究。因此，通过产生具有潜在药用价值的化合物并促进适用于广泛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影响。