SPONTANEOUS DIKETOPIPERAZINE FORMATION VIA END-TO-END CYCLIZATION OF A NONACTIVATED LINEAR TRIPEPTIDE - AN UNUSUAL CHEMICAL-REACTION
SPONTANEOUS DIKETOPIPERAZINE FORMATION VIA END-TO-END CYCLIZATION OF A NONACTIVATED LINEAR TRIPEPTIDE - AN UNUSUAL CHEMICAL-REACTION
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DOI：
10.1021/ja00098a003
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发表时间：
1994-09-21
影响因子：
15
通讯作者：
SCHILLER, PW
中科院分区：
文献类型：
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作者：
CARPENTER, KA;WELTROWSKA, C;SCHILLER, PW
δ-阿片拮抗剂 H-Tyr-Tic Psi[CH2-NH]Phe-OH（TIP[Psi]，Tic = 四氢异喹啉-3-羧酸）在 DMSO 和 MeOH 中自发形成 N-(Mti)-Phe-Tyr 二酮哌嗪（Mti = [(3'S)-四氢异喹啉基]甲基），但在水溶液或 DMSO:H2O 中则不然至少含有 20% 水的溶剂混合物。所提出的二酮哌嗪形成反应机制涉及未活化线性三肽的 N 和 C 端基之间形成酰胺键，然后仲胺对 Tyr 羰基进行跨环亲核攻击。对 TIP[Psi] 进行的分子力学计算揭示了分子可用的低能结构，其中羧基和氨基末端官能团在适合亲核攻击的距离内 (2.8 埃)。二酮哌嗪的形成速率显示出取决于样品 pH 值和末端肽氨基的亲核性。在 HPLC 分析或 NMR 研究期间，没有观察到与二酮哌嗪处于互变异构平衡的反应中间体或其他化合物。从TIP[Psi]获得的二酮哌嗪被分离并通过H-1 NMR光谱结合分子建模进行结构表征。根据 H-1 NMR 耦合常数，二酮哌嗪环周围侧链的几种方向是可能的。 Tyr beta 和 Mti 亚甲基质子与预期值的大化学位移位移可以用稳定低能结构的芳族相互作用所体现的环电流效应来解释。计算出的二酮哌嗪环结构稍微偏离平面-5度至-15度。
The delta-opioid antagonist H-Tyr-Tic Psi[CH2-NH]Phe-OH (TIP[Psi], Tic = tetrahydroisoquinoline-3-carboxylic acid) was shown to undergo spontaneous formation of N-(Mti)-Phe-Tyr diketopiperazine (Mti = [(3'S)-tetrahydroisoquinolinyl] methyl) in DMSO and MeOH but not in aqueous solution or DMSO:H2O solvent mixtures which were at least 20% water. The reaction mechanism proposed for the diketopiperazine formation involves amide bond formation between the N and C terminal groups of the nonactivated linear tripeptide, followed by transannular nucleophilic attack of the Tyr carbonyl group by the secondary amine. Molecular mechanics calculations carried out on TIP[Psi] revealed low-energy structures available to the molecule in which the carboxyl and amino terminal functions are within a distance suitable for nucleophilic attack (2.8 Angstrom), The rate of diketopiperazine formation was shown to be dependent on both sample pH and nucleophilicity of the terminal peptide amino group. Reaction intermediates or additional compounds in tautomeric equilibria with the diketopiperazine were not observed during the HPLC analyses or NMR investigations. The diketopiperazine obtained from TIP[Psi] was isolated and structurally characterized by H-1 NMR spectroscopy in conjunction with molecular modeling. According to H-1 NMR coupling constants, several orientations of the side chains around the diketopiperazine ring are possible. Large chemical shift displacements from expected values observed for the Tyr beta and Mti methylene protons are explained in terms of ring current effects manifested by aromatic interactions which stabilize the low-energy structures. The calculated diketopiperazine ring structure is slightly puckered out of plane by -5 degrees to -15 degrees.