Aebi J D, Deyo D T, Sun C Q, Guillaume D, Dunlap B, Rich D H
School of Pharmacy, University of Wisconsin--Madison 53706.
J Med Chem. 1990 Mar;33(3):999-1009. doi: 10.1021/jm00165a018.
The syntheses of three new cyclosporin A (CsA) analogues that contain novel MeBmt derivatives in the 1-position are described. The MeBmt analogue that contains an additional methyl group on C4, (2S,3R,6E)-4,4-dimethyl-3-hydroxy-2-(N-methylamino)-6-octenoic acid (MeBm2t), was synthesized in four steps beginning with the reaction of Pmz-Sar-OtBu with (4E)-2,2-dimethyl-4-hexenal. The C4 desmethyl analogue of MeBmt, (2S,3R,6E)-3-hydroxy-2-(N-methylamino)-6-octenoic acid (MeBth), was synthesized in nine steps by a route based on the Sharpless chiral epoxidation procedure. The alkynyl derivative of MeBmt, (2S,3R,4R)-4-methyl-3-hydroxy-2-(N-methylamino)-6-octynoic acid (MeByt), was synthesized by a modification of the procedure described by Tung et al. for the synthesis of MeBmt. Each MeBmt analogue was protected as the N,O-acetonide and coupled with the hexapeptide Abu-Sar-MeLeu-Val-MeLeu-Ala-OBzl. The resulting heptapeptide was deprotected and coupled with Fmoc-D-Ala-MeLeu-MeLeu-MeVal-OH. The resulting undecapeptides were deprotected and cyclized to give the corresponding CsA analogues. Conformational analysis by 1D and 2D NMR methods was carried out for each analogue in chloroform, and the results are compared with the corresponding solution conformations of CsA and dihydrocyclosporin. The immunosuppressive activities of each analogue, determined in concanavalin A stimulated thymocytes, are lower than obtained for CsA. The results establish the important effect the methyl group and the double bond in MeBmt have on the solution conformation of the 1-position residue in CsA and on immunosuppressive activity.
描述了三种新的环孢菌素A（CsA）类似物的合成，这些类似物在1位含有新型MeBmt衍生物。在C4上含有额外甲基的MeBmt类似物，即(2S,3R,6E)-4,4-二甲基-3-羟基-2-(N-甲基氨基)-6-辛烯酸（MeBm2t），从Pmz-Sar-OtBu与(4E)-2,2-二甲基-4-己烯醛反应开始，经四步合成。MeBmt的C4去甲基类似物，即(2S,3R,6E)-3-羟基-2-(N-甲基氨基)-6-辛烯酸（MeBth），通过基于Sharpless手性环氧化程序的路线经九步合成。MeBmt的炔基衍生物，即(2S,3R,4R)-4-甲基-3-羟基-2-(N-甲基氨基)-6-辛炔酸（MeByt），通过对Tung等人描述的合成MeBmt的程序进行修改而合成。每个MeBmt类似物都被保护为N,O-丙酮化物，并与六肽Abu-Sar-MeLeu-Val-MeLeu-Ala-OBzl偶联。所得七肽脱保护后与Fmoc-D-Ala-MeLeu-MeLeu-MeVal-OH偶联。所得十一肽脱保护并环化以得到相应的CsA类似物。在氯仿中对每个类似物进行了一维和二维核磁共振方法的构象分析，并将结果与CsA和二氢环孢菌素的相应溶液构象进行了比较。在伴刀豆球蛋白A刺激的胸腺细胞中测定的每个类似物的免疫抑制活性低于CsA。结果证实了MeBmt中的甲基和双键对CsA中1位残基的溶液构象和免疫抑制活性具有重要影响。
