DIAZONAMIDE SYNTHESIS:A MODEL FOR PEPTIDE METAMORPHOSIS

二氮酰胺合成：肽变态模型

• 批准号: 6039016
• 负责人: Patrick G. Harran
• 金额: $ 26.36万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6039016
• 关键词: biological products; biotin; carbopolycyclic compound; chemical structure function; combinatorial chemistry; cyclization; cytotoxicity; growth inhibitors; lactams; molecular rearrangement; peptide analog; peptide chemical synthesis; peptide library; posttranslational modifications; synthetic peptide; biological products; biotin; carbopolycyclic compound; chemical structure function; combinatorial chemistry; cyclization; cytotoxicity; growth inhibitors; lactams; molecular rearrangement; peptide analog; peptide chemical synthesis; peptide library; posttranslational modifications; synthetic peptide

Diazonamide A is a polycyclic secondary metabolite which potently inhibits the growth of a transformed human cell line in vitro. The molecular basis for this activity is unknown. This research seeks to provide synthetic resources necessary for probing diazonamide function and, simultaneously, those of general utility in alternate small molecule discovery programs. The diazonamide structure can be viewed either as a collection of attachable components or as an extensively modified linear pentapeptide. In line with the former, strategies are outlined to assemble the diazonamide skeleton from four fragments including: two alpha-amino acids, a 2-ethynylphenol, and serotonin. A Heck endocyclization / ring-contracting rearrangement sequence installs the C10 quaternary center in diazonamide segment 71. The last fragment (serotonin) is incorporated and the natural framework is completed via orthophenolic coupling to form the C16/C18 biaryl linkage. Tagging for biochemical analysis is outlined for a series of ascending intermediates. Three components and a partial sequence used in diazonamide synthesis form the basis of heterotriarylethylene libraries (103 - 106 members) built using both combinatorial and parallel synthesis techniques. Diazonamides are bioactive metabolites derived from peptides via chemical modification. A conceptually similar, but completely synthetic, strategy is proposed to access complex natural product-like molecules randomly from parallel libraries of short oligopeptides. Five to seven residue natural / artificial hybrid oligopeptides are synthesized on the surface of glass through a photolabile linker. Four types of chemical modifications are explored on intact peptides 1) alkynylation and vinylation with functionalized triflones 2) dehydrative cyclization of serine and cysteine motifs to oxazolines and thiazolines, respectively 3) oxidative intrachain coupling of aromatic residues and 4) metathetical cyclization between proximate olefins. Multiple modifications run in sequence on parallel libraries of pure oligopeptides followed by photorelease is a renewable screening resource for identifying small molecules with therapeutic effects on human cells.

重18zonamide A是一种多环代代谢产物，可在体外有效抑制转化的人类细胞系的生长。该活性的分子基础尚不清楚。 这项研究旨在提供探测重18zonamide功能所需的合成资源，同时在替代小分子发现程序中具有一般效用的合成资源。 重18zonamide结构可以视为可连接组件的集合或广泛修饰的线性五肽。 与前者一致，概述了从四个片段中组装大18酰胺骨骼的策略，其中包括：两种α-氨基酸，一个2-乙基苯酚和5-羟色胺。 HECK内循环 /收缩重排序列安装了地重射酰胺段71中的C10季季心中心。最后一个片段（5-羟色胺）结合了，自然框架是通过形成正苯酚偶联完成的，以形成C16 / C18 Biaryl链接。针对一系列上升中间体概述了用于生化分析的标签。 地重射酰胺合成中使用的三个成分和一个部分序列构成了使用组合和平行合成技术构建的杂体甲基乙烯文库（103-106个成员）的基础。重18zonamides是通过化学修饰衍生自肽的生物活性代谢产物。 提出了一种概念上相似但完全合成的策略，以从短寡肽的平行文库中随机获取复杂的天然产物样分子。 五到七个残基天然 /人造杂交寡肽通过光片连接器在玻璃表面合成。 在完整的肽上探索了四种类型的化学修饰1）用官能化的三酮2）分别将丝氨酸和半胱氨酸基序的脱水环化与阿沙唑啉和噻唑啉分别为3）氧化性内液偶联（4）元素含量的环化蛋白（4）氧化肠内耦合之间的脱水环化，分别是链球菌和噻嗪的乙烯基化。 多次修饰在纯寡肽的平行文库中进行顺序进行，然后是光释放酶，是可再生筛选资源，用于鉴定对人类细胞具有治疗作用的小分子。