Synthesis of Peptide Isosteres with Strong Bombesin Antagonist Activity and Its Development to Anti-Cancer Agents

在各种二肽异构体中，(E)-烯二肽异构体（EADIs）作为肽中酰胺键的骨干替代的潜力在过去几年中得到了很好的证明。然而，目前还没有建立有效的立体控制合成路线。我们之前报道了有机铜介导的γ， δ -顺- γ， δ -eepimino-(E)- α， β -enoates或γ， δ -syn- δ -氨基- γ -mesyloxy-(E)- α， β -enoates的抗s_n2 '反应，分别产生L，L型或L， d型EADIs。基于从头计算的分子轨道计算，我们开发了Pd(0)催化的四种非对映体的异构化反应，这些非对映体是由l -氨基酸开始的，可以很容易地得到所需的关键中间体，γ， δ -顺- γ， δ -epimino-(E)- α, β -enoates，产率高。此外，用dil对相同的基质进行了简单的处理。meso3h定量地提供了区域和立体选择性开环产物，γ， δ -syn- δ -氨基- γ -甲氧基-(E)- α, β -enoates。本质上，以同样的方式从D-氨基酸开始，立体选择性合成D，D型和D， l型eadi是可行的。至此，建立了四组同手性EADIs的全立体控制合成路线。应用上述直接合成策略衍生化潜在的肽导抗癌化合物，包括bombesin/GRP拮抗剂和Ras-Farnesyl转移酶抑制剂。

Among various dipeptide isosteres, the potential of (E)-alkene dipeptide isostsres (EADIs) as backbone replacement of amide bonds in peptides has been well documented in the past few years. However, the efficient stereocntrolled synthetic routes for EADIs have not been established. We previously reported the organocopper-mediated anti-S_N2' reactions of gamma, delta-cis-gamma, delta-eepimino-(E)-alpha, beta-enoates or gamma, delta-syn-delta-amino-gamma-mesyloxy-(E)-alpha, beta-enoates, which give L,L-type or L,D-type EADIs respectively. Based on the ab initio molecular orbital calculations, we have developed Pd(0)-catalyzed isomerization reactions of four diastereomixtures of gamma, delta-epimino-alpha, beta-enoates, easily prepared by the sequence of known reactions starting from L-amino acids, which give the desiarble key intermediates, gamma, delta-cis-gamma, delta-epimino-(E)-alpha, beta-enoates, in high yield. Furthermore, a brief treatment of the same substrates with dil. MeSO_3H quantitatively affords the regio-and stereoselectively ring-opened products, gamma, delta-syn-delta-amino-gamma-mesyloxy-(E)-alpha, beta-enoates. Essentially, in the same manner starting from D-amino acids, stereoselective synthesis of D,D-type and D,L-type EADIs is feasible. Thus, the totally stereocontrolled synthetic routes for four sets of homo chiral EADIs have been established.Application of the above straightforward synthetic strategy to derivatization of the potential peptide-lead anti-cancer compounds involving bombesin/GRP antagonist and Ras-Farnesyl transferase inhibitor has been examined.