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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.

本项目综合研究了GE3和polyoxypeptin （A和B）、链霉菌新型19元环六肽抗生素、Papuamides （A和B）、海绵属theonellaa具有抗HIV和细胞毒活性的新型环沉积肽。利用Sharpless的不对称二羟基化和Evan的和Paterson的aldol方法，实现了GE3的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孔，进行了多羟肽酰基侧链段的立体选择性合成。采用RuC_2（binap）催化氢化反应，通过动力学拆分，有效地合成了环沉积肽组分（2R,3R）和(2S, 3S)-羟基亮氨酸及其相应的β-酮-α-氨基酸酯的非对映体，并以SmI_2为关键步骤，采用非对映选择性环化反应，实现了多羟肽组分(2S,3R)-3-羟基-3- ra乙基脯氨酸(2)的立体选择性合成。以(S)-焦谷氨酸为原料，立体选择性地制备了(3S,4R)-3,4-二甲基1-(S)-谷氨酰胺。通过对合成的3,4-二甲基焦谷氨酸与天然产物水解产物的光谱比较，明确了天然二甲基谷氨酰胺的立体结构为(2S,3S,4R)-立体化学。Β-Methoxytyrosine （β-OMeTyr）是一种立体不确定的papuamides成分。为了进行结构测定和总合成，我们分别用(S)和(R)-丝氨酸立体选择性制备了β-(meyr)的所有立体异构体。该实验室正在进一步研究这三种环沉积肽的最终结构。