ブタからの肝臓移植を可能にするセラミド系糖脂質素材の設計とその合成

设计和合成基于神经酰胺的糖脂材料，使猪肝移植成为可能

基本信息

批准号：
11672114
负责人：
KAJIMOTO Tetsuya
金额：
$ 2.3万
依托单位：
Tokyo University of Agriculture and Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

It is known that hyper acute rejection (HAK) which interfere with the xeno-transplantation of organs was caused by excess immune responses between Gala (1,3) Gal antigenic glycoside of porcine liver and the antibody generated in the recipient serum toward the glycoside. In order to develop the novel medical materials for avoiding the HAR, we synthesized mycestericin D and F, potent immune suppressants isolated from Isaria sinclairii, and a UDP-galactose mimetic as an inhibitor of α1,3-galactosyltransferase that biosynthesizes the Galaα(1,3) Gal epitope.1) Synthesis of mycestericinsγBenzyloxybutanal was treated with L-threonine aldolase (from Candida humicola AKU 4586) that catalyzes aldol condensation in the presence of glycine to afford the ε-benzyloxy-α-L-amino acid, of which the methyl ester was transformed to an oxazoline derivative by the reaction with methyl benzimidate. After addition of the C-l unit to the α-orposition of the oxazoline derivative, of which the benzyl ether was transformed to an aldehyde group, the following Wittig reaction and deprotection gave mycestericin D. A subsequent hydrogenation step gave mycestericin F.2) Synthesis of peptidic mimetics of UDP-galactoseL-Threonine aldolase-catalyzed reaction of 2-(l-N-uracily])acetaldehyde and glycine afforded a uracil residue bearing β-hydroxy-α-L-amino acid, of which the benzyl ester was condensed with 2-(l-O-α-galactosyl) hydroxyacetic acid by the DCC / HOBt method to form a peptidic linkage. The following deprotection procedure provided the peptidic mimetics of UDP-galactose.

已知干扰器官异种移植的超急性排斥反应(HAK)是由猪肝脏的Gala(1,3)Gal抗原糖苷与受体血清中产生的针对该糖苷的抗体之间的免疫过度反应引起的。为了开发避免 HAR 的新型医用材料，我们合成了 mycestericin D 和 F（从 Isaria sinclairii 中分离出的有效免疫抑制剂）以及作为 HAR 抑制剂的 UDP-半乳糖模拟物。 ε-苄氧基-α-L-氨基酸，其中通过与苯甲亚胺甲酯反应将甲酯转化为恶唑啉衍生物。在恶唑啉衍生物的α-位上加成C-1单元后，其中的苄基醚转化为醛基，进行以下Wittig反应和脱保护。得到mycestericin D。随后的氢化步骤得到mycestericin F.2) 肽模拟物的合成UDP-半乳糖L-苏氨酸醛缩酶催化2-(l-N-尿嘧啶])乙醛和甘氨酸的反应得到带有β-羟基-α-L-氨基酸的尿嘧啶残基，其中苄酯与2-(l-O-缩合) α-半乳糖基）羟基乙酸通过DCC/HOBt方法形成如下肽键。脱保护程序提供了 UDP-半乳糖的肽模拟物。