DIAZONAMIDE SYNTHESIS:A MODEL FOR PEPTIDE METAMORPHOSIS

重氮酰胺A是一种多环次级代谢物，在体外能有效地抑制转化的人类细胞系的生长。这种活性的分子基础尚不清楚。这项研究试图提供探索重氮胺功能所需的合成资源，同时提供那些在替代小分子发现计划中具有普遍用途的合成资源。重氮酰胺结构可以被视为可连接组分的集合，也可以被视为广泛修饰的线性五肽。根据前者，概述了由四个片段组装重氮胺骨架的策略，包括：两个α-氨基酸、一个2-乙炔基苯酚和5-羟色胺。Heck内环化/缩环重排序列将C10四元中心安装在重氮酰胺链段71中。最后一段(5-羟色胺)被结合，天然骨架通过邻苯酚偶联形成C16/C18联芳键。概述了用于生化分析的一系列上升中间体的标记。重氮胺合成中使用的三个组分和部分序列形成了使用组合和平行合成技术建立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多肽经化学修饰而成的生物活性代谢物。提出了一种概念上相似，但完全合成的策略，从短低聚肽的平行文库中随机获取复杂的天然产物样分子。通过耐光性连接体在玻璃表面合成了5~7个残基的天然/人工杂化寡肽。对完整多肽进行了四种化学修饰：1)与功能化三氟酮的烷基化和乙烯基化；2)丝氨酸和半胱氨酸的脱水环化成恶唑啉和噻唑啉；3)芳香族残基的氧化链内偶联反应；4)近端烯烃之间的歧化环化反应。在纯寡肽的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，用于鉴定对人类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.