O-N intramolecular acyl migration reaction in the development of prodrugs and the synthesis of difficult sequence-containing bioactive peptides
O-N intramolecular acyl migration reaction in the development of prodrugs and the synthesis of difficult sequence-containing bioactive peptides
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DOI：
10.1002/bip.20136
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发表时间：
2004-01-01
期刊：
影响因子：
2.9
通讯作者：
Kiso, Y
中科院分区：
文献类型：
--
作者：
Sohma, Y;Hayashi, Y;Kiso, Y
含Ser或Thr的肽中的N-O分子内酰基迁移是肽化学中众所周知的副反应。它导致酯键和酰胺键的相互转化。我们的药物化学研究集中在这样一个事实，即O-酰基产品可以很容易地转化为原始的N-酰基形式在中性或弱碱性条件下，在水性缓冲液和释放的离子化氨基增强O-酰基产品的水溶性。基于此，我们开发了一类新型的“O-N分子内酰基迁移”型水溶性HIV-1蛋白酶抑制剂前药。这些前药通过简单的化学机制释放母体药物，无副作用。在本研究中，我们将这一策略应用于重要的癌症化疗药物紫杉醇及其衍生物，以开发水溶性紫杉烷前药，并发现这些前药，紫杉烷的2 '-O-异构体，显示出有希望的结果，具有较高的水溶性和适当的动力学，在其母体药物通过一个简单的pH依赖性化学机制与O-N分子内酰基迁移。O-N分子内酰基迁移在药物化学中的成功应用后，最近又被用于肽化学中合成“含难序列肽”。“该策略是基于亲水性O-酰基异肽合成，然后是O-N分子内酰基迁移反应，从而产生所需的肽。在一个模型研究与小，困难的序列含有肽，合成的“O-酰基异肽”不仅提高了在各种介质中的溶解度，有效地进行了高效液相色谱纯化，而且还改变了困难的序列在SPPS过程中的性质，导致在O-酰基异肽的有效合成，没有并发症。纯化的O-酰基异肽的随后的O-N分子内酰基迁移以高产率和高纯度提供作为沉淀物的所需肽。进一步研究合成更大的含难序列肽--阿尔茨海默病相关肽（A β 1 -42），令人惊讶地表明，仅插入一个O-酰基就大大改善了A β 1 -42中困难序列的不利性质，并实现了26-O-酰基异A β 1 -42的有效合成，随后通过26-O-的O-N分子内酰基迁移反应完全转化为AP 1 -42。酰基异A β 1 -42。这表明，我们的新方法基于O-N分子内酰基迁移是一个重要的方法，合成的困难序列的含生物活性肽。(C)2004 Wiley Periodicals，Inc.
N-O intramolecular acyl migration in Ser- or Thr-containing peptides is a well-known side reaction in peptide chemistry. It results in the mutual conversion of ester and amide bonds. Our medicinal chemistry study focused on the fact that the O-acyl product can be readily converted to the original N-acyl form under neutral or slightly basic conditions in an aqueous buffer and the liberated ionized amino group enhances the water solubility of O-acyl products. Because of this, we have developed a novel class of "O-N intramolecular acyl migration"-type water-soluble prodrugs of HIV-1 protease inhibitors. These prodrugs released the parent drugs via a simple chemical mechanism with no side reaction. In this study, we applied this strategy to important cancer chemotherapeutic agents, paclitaxel and its derivatives, to develop water-soluble taxoid prodrugs, and found that these prodrugs, 2'-O-isoform of taxoids, showed promising results with higher water solubility and proper kinetics in their parent drug formation by a simple pH-dependent chemical mechanism with O-N intramolecular acyl migration. These results suggest that this strategy would be useful in toxicology and medical economics.After the successful application of O-N intramolecular acyl migration in medicinal chemistry, this concept was recently used in peptide chemistry for the synthesis of "difficult sequence-containingpeptides." The strategy was based on hydrophilic O-acyl isopeptide synthesis followed by the O-N intramolecular acyl migration reaction, leading to the desired peptide. In a model study with small, difficult sequence-containing peptides, synthesized "O-acyl isopeptides" not only improved the solubility in various media and efficiently performed the high performance liquid chromatography purification, but also altered the nature of the difficult sequence during SPPS, resulting in the efficient synthesis of O-acyl isopeptides with no complications. The subsequent O-N intramolecular acyl migration of purified O-acyl isopeptides afforded the desired peptides as precipitates with high yield and purity. Further study of the synthesis of a larger difficult sequence-containing peptide, Alzheimer's disease-related peptide (Abeta1-42), surprisingly showed that only one insertion of the O-acyl group drastically improved the unfavorable nature of the difficult sequence in Abeta1-42, and achieved efficient synthesis of 26-O-acyl isoAbeta1-42 and subsequent complete conversion to AP1-42 via the O-N intramolecular acyl migration reaction of 26-O-acyl isoAbeta1-42. This suggests that our new method based on O-N intramolecular acyl migration is an important method for the synthesis of difficult sequence-containing bioactive peptides. (C) 2004 Wiley Periodicals, Inc.