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

目前已知，干扰异种器官移植的超急性排斥反应（HAK）是由猪肝Gala (1,3) Gal抗原糖苷与受体血清中针对该糖苷产生的抗体之间的过度免疫反应引起的。为了开发避免HAR的新型医用材料，我们合成了从Isaria sinclairii中分离的有效免疫抑制剂mycestericin D和F，以及作为α1,3-半乳糖转移酶抑制剂的udp -半乳糖模拟物，其生物合成了Galaα(1,3) Gal表位。1)利用l -苏氨酸醛缩酶（产自humicola假丝酵母AKU 4586）在甘氨酸存在下催化醛缩生成ε-苯并氧基-α- l氨基酸，并与苯并咪酯反应生成恶唑啉衍生物。在恶唑啉衍生物的α-羟基上加入c - 1单元，其中苯醚转化为醛基，接下来的Wittig反应和脱保护得到菌酯素d，随后的加氢步骤得到菌酯素f。2)合成udp -半乳糖-苏氨酸醛缩酶催化的2-（l- n -醛酸）乙醛和甘氨酸的肽模拟物，得到含有β-羟基-α- l-氨基酸的尿嘧啶残基。其中苄酯与2-（l-O-α-半乳糖）羟基乙酸通过DCC / HOBt法缩合形成肽链。下面的去保护程序提供了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.