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Synthesis of Cell-cycle Inhibitory Peptides and Their Development for Medicinal Use

细胞周期抑制肽的合成及其药用开发

基本信息

批准号：
11557171
负责人：
HAMADA Yasumasa
金额：
$ 4.86万
依托单位：
CHIBA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2002
项目状态：
已结题

项目摘要

In this project, GE3 and Polyoxypeptins (A and B), novel 19-membered cyclic hexadepsipeptide antibiotics from Streptcmyces strains and Papuamides (A and B), novel cyclodepsipeptides with anti HIV and cytotoxic activies from the marine sponge genus Theonellawere synthetically studied. Stereoselective synthesis of the acyl side chain segment of GE3 has been achieved by using Sharpless's asymmetric dihydroxylation and stereoselective Evan's and Paterson's aldol methodologies. Stereoselective synthesis of the acyl side chain segment of Polyoxypeptins has been carried out through regioselective opening of chiral 2,3-epoxyalcohol. (2R,3R)-and (2S, 3S)-Hydroxyleucines, components of the cyclodepsipeptides, were efficiently synthesized along with their diastereomers from the corresponding β-keto-α-amino acid ester through dynamic kinetic resolution using RuC_2(binap) catalyzed hydrogenation, Stereoselective synthesis of (2S,3R)-3-hydroxy-3-raethylproline (2), a component of polyoxypeptins, has been achieved by use of diastereoselective cyclization reaction using SmI_2 as a key step. (3S,4R)-3,4-Dimethy1-(S)-glutamine,a component Papuamides, was stereoselectively prepared from (S)-pyroglutamic acid. The stereostructure of natural dimethylglutamine was unambiguously confirmed to be (2S,3S,4R)-stereochemistry by comparisons of their spectra of the synthetic 3,4-dimethylpyroglutamic acid with the hydrolysate from the natural product. Β-Methoxytyrosine (β-OMeTyr) is a stereoundefined component of papuamides. For structural determination and total synthesis of papuamides, all stereoisomers of β-(MeTyr were stereoselectively prepared from (S)-and (R )-serine, respectively.Further studies on final construction of the three cyclodepsipeptides are under investigation in this laboratory.

在该项目中，综合研究了GE3和聚氧肽（A和B）、来自链霉菌菌株的新型19元环己缩酚肽抗生素和巴布酰胺（A和B）、来自海洋海绵属Theonella的具有抗HIV和细胞毒活性的新型环缩酚肽。 GE3 酰基侧链片段的立体选择性合成是通过使用 Sharpless 的不对称二羟基化和立体选择性 Evan 和 Paterson 的醇醛缩合方法实现的。聚氧肽素的酰基侧链片段的立体选择性合成是通过手性2,3-环氧醇的区域选择性打开来进行的。使用RuC_2(binap)催化氢化，通过动态动力学拆分，从相应的β-酮-α-氨基酸酯中有效地合成了环缩肽的成分(2R,3R)-和(2S,3S)-羟基亮氨酸及其非对映体，立体选择性合成 (2S,3R)-3-羟基-3-ra乙基脯氨酸(2)是聚氧肽素的组成部分，是通过以SmI_2为关键步骤的非对映选择性环化反应得到的。 (3S,4R)-3,4-二甲基1-(S)-谷氨酰胺是巴布酰胺的一种成分，由(S)-焦谷氨酸立体选择性制备而成。通过比较合成的3,4-二甲基焦谷氨酸与天然产物水解产物的光谱，明确证实天然二甲基谷氨酰胺的立体结构为(2S,3S,4R)-立体化学。 β-甲氧基酪氨酸 (β-OMeTyr) 是巴布酰胺的立体未定义成分。为了巴布酰胺的结构测定和全合成，分别从(S)-和(R)-丝氨酸立体选择性地制备了β-(MeTyr)的所有立体异构体。本实验室正在对三种环缩肽的最终构建进行进一步的研究。