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

超急性排斥反应（hyperacuterejection，HAK）是由猪肝Gala（1，3）Gal抗原性糖苷与受体血清中产生的抗该糖苷的抗体之间产生的过度免疫反应引起的，它会干扰异种器官移植。为了开发新的抗HAR的药物材料，我们合成了从辛氏棒束孢菌中分离的有效免疫抑制剂mycestericin D和F，以及作为α 1，3-半乳糖基转移酶抑制剂的UDP-半乳糖模拟物，该酶生物合成Galaα（1，3）Gal表位。1）合成mycestericinsγ-苄氧基丁醛（来自腐质假丝酵母AKU 4586），其在甘氨酸的存在下催化羟醛缩合以提供ε-苄氧基-α-L-氨基酸，其甲酯通过与苯甲酰亚胺甲酯反应转化为恶唑啉衍生物。在恶唑啉衍生物的α-位上加入C-1单元，使苄醚转化为醛基，然后进行Wittig反应和脱保护得到mycestericin D。2）UDP-半乳糖-苏氨酸醛缩酶催化2-（1-N-尿嘧啶）乙醛和甘氨酸反应，得到一个带有β-羟基-α-L-氨基酸的尿嘧啶残基，其苄酯与2-（1-O-α-半乳糖基）羟基乙酸通过DCC / HOBt方法缩合形成一个肽键。以下脱保护程序提供UDP-半乳糖的肽模拟物。

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.