Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols
Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols
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DOI：
10.1021/jm000173z
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发表时间：
2000-07-27
影响因子：
7.3
通讯作者：
Fujita, T
中科院分区：
文献类型：
--
作者：
Kiuchi, M;Adachi, K;Fujita, T
合成了一系列2-取代的2-氨基丙烷-1,3-二醇，并对其在大鼠同种异体皮肤移植中的淋巴细胞减少作用和免疫抑制作用进行了评价。在先导化合物3的烷基链上引入一个苯环，先导化合物3是由肉豆蔻素（1,isp - 1）经化合物2简化而成的免疫抑制剂。各种化合物的效力取决于苯基环在烷基侧链中的位置。季碳原子与苯环之间的最适宜长度为2个碳原子。相继合成了2-取代2-氨基乙醇，并利用大鼠腘窝淋巴结增重法评价其t细胞减少作用和免疫抑制作用。第四碳的绝对构型影响活性，化合物6的(pro-S)-羟甲基对其免疫抑制活性至关重要。6的（前r）-羟甲基的有利取代基是羟基烷基（羟乙基和羟丙基）或更低的烷基（甲基和乙基）。2-氨基-2-[2-（4-乙酰苯基）乙基]丙烷-1,3-二醇盐酸盐（6,FTY720）具有相当大的活性，有望作为器官移植的免疫抑制药物。
A series of 2-substituted 2-aminopropane-1,3-diols was synthesized and evaluated for their lymphocyte-decreasing effect and immunosuppressive effect on rat skin allograft. A phenyl ring was introduced into the alkyl chain of the lead compound 3, which is an immunosuppressive agent structurally simplified from myriocin (1, ISP-I) via compound 2. The potency of the various compounds was dependent upon the position of the phenyl ring within the alkyl side chain. The most suitable length between the quaternary carbon atom and the phenyl ring was two carbon atoms. 2-Substituted 2-aminoethanols were successively synthesized and evaluated for their T-cell-decreasing effect and immunosuppressive effect using a popliteal lymph node gain assay in rats. The absolute configuration at the quaternary carbon affected the activity, and the (pro-S)-hydroxymethyl group of compound 6 was essential for patent immunosuppressive activity. Favorable substituents for the (pro-R)-hydroxymethyl group of 6 were hydroxyalkyl (hydroxyethyl and hydroxypropyl) or lower alkyl (methyl and ethyl) groups. 2-Amino-2-[2-(4-actylphenyl)ethyl]propane-1,3-diol hydrochloride (6, FTY720) was found to possess considerable activity and is expected to be useful as an immunosuppressive drug for organ transplantation.