Wagner R, Rhoades T A, Or Y S, Lane B C, Hsieh G, Mollison K W, Luly J R
Abbott Laboratories, Pharmaceutical Products Division, Abbott Park, Illinois 60064, USA.
J Med Chem. 1998 May 21;41(11):1764-76. doi: 10.1021/jm960066y.
The potent immunosuppressant ascomycin (1b) was selectively alkylated at the C-32 carbinol, thus providing esters and amides of 32-ascomycinyloxyacetic acid (4, AOAA). These compounds present structural variation at the FKBP/calcineurin interface. While the native carboxylic acid 4 shows no activity in vitro, esters and simple amides of 4 exhibit potent immunosuppression in the human MLR assay. Moreover, amides show inhibitory activity in the rat popliteal lymph node hyperplasia assay. Surprisingly, FKBP binding was weakened by several orders of magnitude when secondary hydrophobic aryl amides of 4 were tested, while maintaining potent immunosuppressive efficacy in vitro.
强效免疫抑制剂子囊霉素（1b）在C-32位甲醇处被选择性烷基化，从而得到32-子囊霉素氧基乙酸（4，AOAA）的酯和酰胺。这些化合物在FKBP/钙调神经磷酸酶界面处呈现结构变化。虽然天然羧酸4在体外无活性，但4的酯和简单酰胺在人混合淋巴细胞反应试验中表现出强效免疫抑制作用。此外，酰胺在大鼠腘窝淋巴结增生试验中显示出抑制活性。令人惊讶的是，当测试4的仲疏水芳基酰胺时，FKBP结合减弱了几个数量级，同时在体外保持强效免疫抑制效力。
