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

强铃蟾肽拮抗活性肽等排体的合成及其抗癌药物的开发

基本信息

批准号：
08457621
负责人：
FUJII Nobutaka
金额：
$ 4.35万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

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.

在各种二肽电子等排体中，(E)-烯烃二肽电子等排体 (EADI) 作为肽中酰胺键主链替代的潜力在过去几年中已得到充分证明。然而，EADI 的有效立体控制合成路线尚未建立。我们之前报道了有机铜介导的γ、δ-顺-γ、δ-eepimino-(E)-α、β-烯酸酯或γ、δ-顺-δ-氨基-γ-甲磺氧基-( E)-α、β-烯酸，分别产生L,L-型或L,D-型EADI。基于从头算分子轨道计算，我们开发了 γ、δ-表亚氨基-α、β-烯酸酯的四种非对映混合物的 Pd(0) 催化异构化反应，可通过从 L-氨基酸开始的已知反应序列轻松制备，以高产率得到理想的关键中间体 γ、δ-顺式-γ、δ-表亚氨基-(E)-α、β-烯酸酯。此外，用 dil 对相同的基材进行简单处理。 MeSO_3H 定量地提供区域选择性和立体选择性开环产物，γ，δ-顺-δ-氨基-γ-甲磺氧基-(E)-α，β-烯酸酯。本质上，以相同的方式从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。因此，已经建立了四组同手性 EADI 的完全立体控制的合成路线。应用上述简单的合成策略来衍生化涉及铃蟾肽/GRP 拮抗剂和 Ras-Farnesyl 转移酶抑制剂的潜在肽先导抗癌化合物。检查了。