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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.

本项目对从链霉菌属中分离得到的新型19元环六缩肽类抗生素GE 3和Polyoxypeptin（A和B）以及从海绵属Theonella中分离得到的具有抗HIV和细胞毒活性的新型环缩肽Papuamides（A和B）进行了合成研究。利用Sharpless的不对称二羟基化反应和立体选择性的Evan和Paterson的羟醛缩合方法，实现了GE 3酰基侧链段的立体选择性合成。通过手性2，3-环氧醇的区域选择性开环，实现了多羟肽酰基侧链的立体选择性合成。(2R以β-酮基-α-氨基酸酯为原料，用RuC_2（binap）催化氢化，通过动态动力学拆分，高效地合成了环缩肽组分（2S，3R）-和（2S，3S）-羟基亮氨酸及其非对映体。立体选择性合成了多氧肽组分（2S，3R）-3-羟基-3-甲基脯氨酸（2），以SmI_2为关键步骤，通过非对映选择性环化反应，实现了对映选择性环化反应。(3S以（S）-焦谷氨酸为原料，立体选择性地合成了Papuamides的组分（4 R）-3，4-二甲基-（S）-谷氨酰胺。通过比较天然产物3，4-二甲基焦谷氨酸与其水解产物3，4-二甲基焦谷氨酸的光谱，确定天然产物二甲基谷氨酰胺的立体结构为（2S，3S，4 R）-立体化学。Β-甲氧基酪氨酸（β-OMeTyr）是papuamides的立体不确定组分。为了进行结构测定和papuamides的全合成，本实验室分别以（S）-和（R）-丝氨酸为原料，立体选择性地合成了β-（MeTyr）的所有立体异构体。