DIAZONAMIDE SYNTHESIS:A MODEL FOR PEPTIDE METAMORPHOSIS

重氮酰胺A是一种多环次级代谢产物，在体外可有效抑制转化的人细胞系的生长。这种活性的分子基础尚不清楚。 本研究旨在提供探测重氮酰胺功能所需的合成资源，同时，在替代小分子发现计划中具有通用性的合成资源。 重氮酰胺结构可以被视为可连接组分的集合或被视为广泛修饰的线性五肽。 与前者一致，概述了从四个片段组装重氮酰胺骨架的策略，包括：两个α-氨基酸，2-乙炔基苯酚和5-羟色胺。 Heck内环化/缩环重排序列在重氮酰胺片段71中安装C10季中心。 最后一个片段（5-羟色胺）被掺入，天然框架通过邻位酚偶联完成，形成C16/C18联芳基键。为一系列提升中间体概述了生化分析的标记。 重氮酰胺合成中使用的三种组分和部分序列形成了使用组合和平行合成技术构建的杂三芳基乙烯文库（103 - 106个成员）的基础。重氮酰胺类化合物是由肽类化合物通过化学修饰而得到的具有生物活性的代谢产物。 一个概念上类似的，但完全合成的，战略提出了访问复杂的天然产物样分子随机从平行库的短寡肽。 在玻璃表面通过光不稳定的连接基团合成5 - 7个残基的天然/人工杂合寡肽。 在完整肽上探索了四种类型的化学修饰：1）用官能化的三氟甲酮进行炔基化和乙烯基化; 2）丝氨酸和半胱氨酸基序分别脱水环化为恶唑啉和噻唑啉; 3）芳族残基的氧化链内偶联;以及4）邻近烯烃之间的复分解环化。 在纯寡肽的平行文库上依次进行多个修饰，然后进行光释放，是用于鉴定对人类细胞具有治疗作用的小分子的可再生筛选资源。

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.