DIAZONAMIDE SYNTHESIS:A MODEL FOR PEPTIDE METAMORPHOSIS

重氮酰胺A是一种多环次生代谢物，能有效抑制体外转化的人细胞系的生长。这种活性的分子基础尚不清楚。本研究旨在为探测重氮酰胺功能提供必要的合成资源，同时，在其他小分子发现程序中具有一般效用的合成资源。重氮酰胺的结构既可以看作是一组可附着的组分，也可以看作是一种被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，一个2-乙基苯酚和5 -羟色胺。Heck内环化/环收缩重排序列将C10季中心安装在重氮酰胺第71段。最后一个片段（5 -羟色胺）被结合，通过正酚偶联形成C16/C18联芳键完成自然框架。标记生化分析概述了一系列上升中间体。三组分和部分序列用于重氮酰胺合成形成杂三芳烯库（103 - 106个成员）的基础上，利用组合和平行合成技术建立。重氮酰胺是由多肽经化学修饰而产生的具有生物活性的代谢物。一个概念上类似的，但完全合成的策略，提出了从短寡肽平行文库随机获取复杂的天然产物样分子。在玻璃表面通过可光性连接剂合成了5 ~ 7种残留的天然/人工杂化寡肽。对完整肽进行了四种类型的化学修饰：1)功能化三氟酮的炔基化和乙烯基化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)芳香残基的链内氧化偶联4)邻烯烃之间的甲基环化。在纯寡肽平行文库上按顺序进行多重修饰，然后进行光释放，是一种可再生的筛选资源，用于鉴定对人体细胞具有治疗作用的小分子。

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.