Kinetics of acid-catalyzed degradation of cyclosporin A and its analogs in aqueous solution.
Kinetics of acid-catalyzed degradation of cyclosporin A and its analogs in aqueous solution.
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水溶液中环孢菌素 A 及其类似物的酸催化降解动力学。
DOI：
10.1111/j.1399-3011.1994.tb00386.x
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Stella,VJ
中科院分区：
文献类型：
--
作者：
Oliyai,R;Safadi,M;Meier,PG;Hu,MK;Rich,DH;Stella,VJ
研究了环孢菌素A在酸性水溶液中的降解动力学和机理。在研究的pH值范围内（1-4），降解速率具有特定的酸催化作用，异环孢菌素A为主要降解产物。选择性还原氨基酸2-N-甲基-（R）-（（E）-2-丁烯基）-4-甲基-l-苏氨酸（MeBmt）的烯键不会影响环孢菌素A的总体降解动力学和产物分布。这些观察结果表明，涉及分子内烷氧基加成到氨基酸MeBmt的烯键的替代降解途径显然对环孢菌素A在pH范围1-4内的总体降解动力学没有显著贡献。考察了O-乙酰基-环孢菌素A的化学反应性，以探索环孢菌素A异构化的控制机制。在相同条件下，O-乙酰基-环孢菌素A显示出比环孢菌素A更高的化学稳定性，这与涉及羟基恶唑烷中间体的机制一致。还检查了含有两个β-羟基的环孢菌素C的化学稳定性。环孢菌素C降解的速率和产物分布表明，在酸性水溶液条件下，其仅在氨基酸残基MeBmt处发生N，O-酰基迁移。此外，通过研究一系列环孢菌素A类似物的降解动力学来检查氨基酸MeBmt的侧链体积的影响。这些类似物异构化的表观速率常数与环孢菌素A的表观速率常数没有显著差异，表明氨基酸MeBmt的末端体积可能在控制环孢菌素A中N，O-酰基迁移的速率和程度方面不起关键作用。
The kinetics and mechanism of the degradation of cyclosporin A have been studied under aqueous acidic conditions. The rate of degradation was found to be specific acid‐catalyzed over the pH range studied (1–4), with isocyclosporin A as the predominant degradation product. Selective reduction of the olefinic bond of the amino acid 2‐N‐methyl‐(R)‐((E)‐2‐butenyl)‐4‐methyl‐l‐threonine (MeBmt) did not affect the overall degradation kinetics and product distribution of cyclosporin A. These observations indicate that the alternative degradation pathway involving intramolecular alkoxy addition to the olefinic bond of amino acid MeBmt apparently does not significantly contribute to the overall degradation kinetics of cyclosporin A in the pH range 1–4. The chemical reactivity ofO‐acetyl‐cyclosporin A was examined to probe the governing mechanism for the isomerization of cyclosporin A. Under identical conditions,O‐acetyl‐cyclosporin A showed a much greater chemical stability than cyclosporin A, consistent with a mechanism involving the hydroxyoxazolidine intermediate. The chemical stability of cyclosporin C, which contains two β‐hydroxyl groups, was also examined. The rate and product distribution for the degradation of cyclosporin C suggest that under aqueous acidic conditions it undergoesN,O‐acyl migration solely at the amino acid residue MeBmt. Additionally, the impact of side‐chain bulkiness of amino acid MeBmt was examined by studying the degradation kinetics of a series of cyclosporin A analogs. The apparent rate constants for the isomerization of these analogs were not significantly different from that of cyclosporin A, indicating that the terminal bulkiness of amino acid MeBmt may not play a critical role in controlling the rate and extent ofN,O‐acyl migration in cyclosporin A.