Nowadays, the chemical conjugation to mPEG, also known as PEGylation, is a well‐recognized technology used to improve the pharmaceutical properties of the therapeutic proteins. Over the last 20 years, more than 10 PEGylated macromolecules reached the market with tremendous success, whereas various other bioconjugates are under advanced clinical trials. mPEG–N‐hydroxysuccinimidyl carbonate is an important reagent of widespread application for the PEGylation of biomacromolecules. One of the most important challenges in this technology is the development of more selective PEGylation reagents aimed to provide more consistent polymer–protein conjugates. One approach followed to improve the selectivity of PEGylation reagents is the design of less reactive derivatives, for example, by incorporation of alkyl spacers between the polymer chain and the terminal reactive group. In this work, we prepared a family of mPEG–N‐hydroxysuccinimidyl carbonates bearing spacers of up to 6 carbon atoms. The kinetics of hydrolysis of the carbonates was studied under different experimental conditions, as a straight measure of the influence of the length of the spacer on the reactivity. By DFT calculations, we propose a detailed mechanism for the hydrolysis reaction. The influence of the length of alkyl spacer on the reactivity of the carbonates and related esters is studied and discussed in detail. Finally, to further evaluate the reactivity, selected N‐hydroxysuccinimidyl carbonates were studied in the conjugation reaction of bovine lactoferrin. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 47028.

中文翻译：

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mPEG–NHS碳酸盐：烷基间隔基对反应性的影响：动力学和机理的见解

如今，与mPEG的化学结合（也称为PEG化）是一种公认​​的技术，用于改善治疗性蛋白质的药物特性。在过去的20年中，超过10种PEG化的大分子成功进入市场，而其他各种生物缀合物也正在接受先进的临床试验。mPEG– N碳酸羟基琥珀酰亚胺酯是生物大分子聚乙二醇化的重要应用试剂。这项技术中最重要的挑战之一是开发更具选择性的聚乙二醇化试剂，旨在提供更一致的聚合物-蛋白质结合物。改善PEG化试剂选择性的一种方法是设计反应性较低的衍生物，例如，通过在聚合物链和末端反应性基团之间引入烷基间隔基。在这项工作中，我们准备了一个mPEG– N家族带有多达6个碳原子的间隔基的碳酸-羟基琥珀酰亚胺基碳酸酯。在不同的实验条件下研究了碳酸盐的水解动力学，以此作为衡量间隔物长度对反应性影响的直接指标。通过DFT计算，我们提出了水解反应的详细机理。研究和讨论了烷基间隔基的长度对碳酸酯和相关酯的反应性的影响。最后，为进一步评估反应性，在牛乳铁蛋白的共轭反应中研究了选定的N-羟基琥珀酰亚胺碳酸酯。©2018 Wiley Periodicals，Inc.J.应用 Polym。科学 2019，136，47028。