Dial-a-macrocycle: a SuRE way to access macrocyclic peptides

这项研究涉及一种全新的方法来制造一组被称为大环的分子，大环被定义为包含12个或更多原子的环的任何化学物质。大环化合物在许多科学学科中具有重要的应用，并且与这项工作特别相关的是，它们在药物发现中具有很大的潜力。这得到了超过100种已知大环药物（例如抗生素红霉素）的存在的支持，但是，如果不是因为大环通常非常难以制备的简单事实，这个数字无疑会大得多。事实上，在这100种已知的大环药物中，几乎所有的药物都是由自然界提供的，只有很少一部分是在实验室合成的。传统上，大环通过在长线性分子的两个“末端”之间形成化学键来制备，但是竞争反应和副产物形成通常占主导地位，这意味着这样的过程通常是低效的。这项研究是基于一种新的大环合成系统，其中完全避免了困难的大环化步骤，相反，大环是通过较小环系统的迭代扩展“生长”的，通过一个称为连续环扩展（SuRE）的过程。一个较小的环状分子经过简单的化学转化，将一个线性分子连接到它上面。然后，用于促进一种新的化学反应（或重排），使线性分子插入到原来的环（现在已经增加了大小！）。反应设计中的一个关键因素是存在于原始环中的化学基团在扩大的产物中复制，因此可以用新的连接基重复相同的一系列步骤以形成更大的环;实际上，该序列理论上可以无限重复，从而可以制备几乎任何环尺寸和组成的大环化合物。将开发用于产生医学上重要的大环肽（其与蛋白质化学相关）的新型SuRE反应系统。大环肽在药物化学中是当前非常感兴趣的，特别是因为它们已被证明对更传统的小分子药物/药剂治疗效果差的生物靶标有效。然而，大环肽难以使用公开的方法（特别是大规模）制备的事实是该领域进展的主要障碍。初步结果表明，新的SuRE反应概述的建议将是高产率和易于进行实验。它也预计将是广泛的范围，从而允许药物化学家设计和制造新的大环肽药物候选人比目前可能的更大的自由。此外，由于预期SuRE方法同样适用于小规模和大规模合成，因此如果鉴定出具有有希望的药用特性的任何大环肽，则其应用作扩大（甚至可能生产）生物活性药物成分的方法。

This research concerns a fundamentally new approach to make a group of molecules known as macrocycles, which are defined as any chemical species containing a ring of 12 or more atoms. Macrocycles have important applications in a number of scientific disciplines and, of particular relevance to this work, they have much potential in drug discovery. This is backed up by the existence of over 100 known macrocycle drugs (e.g. the antibiotic erythromycin) but, this number would undoubtedly be far greater if not for the simple fact that macrocycles are usually very difficult to make. Indeed, it is telling that of these 100 known macrocyclic drugs, almost all are provided by Nature, with very few being made synthetically in the lab. Traditionally, macrocycles are made by forming a chemical bond between the two 'ends' of a long linear molecule, but competing reactions and side product formation typically dominate, meaning that such processes are usually inefficient. This research is based on a new system for macrocycle synthesis in which the difficult macrocyclisation step is completely avoided, and instead, macrocycles are 'grown' via the iterative expansion of smaller ring systems, via a process called Successive Ring Expansion (SuRE).In SuRE, a smaller cyclic molecule undergoes a simple chemical transformation to attach a linear molecule onto it. A reactive group built into this new postion is then used to promote a novel chemical reaction (or rearrangement) such that the linear molecule inserts itself into the original ring (which has now increased in size!). A crucial factor in the reaction design is the fact that the chemical groups present in the original ring are replicated in the enlarged product, therefore the same series of steps can then be repeated with a new linker to form an even larger ring; indeed, the sequence can theoretically be repeated indefinitely, allowing of macrocycles of virtually any ring size and composition to be made.In this work, a novel SuRE reaction system for the generation of medicinally important macrocyclic peptides (which are chemically related to proteins) will be developed. Macrocyclic peptides are of much current interest in medicinal chemistry, especially as they have proven efficacy against biological targets that are poorly treated by more traditional small molecule drugs/pharmaceutical agents. However, the fact that macrocyclic peptides are difficult to make using published methods (especially on large scale) is a major barrier to progress in this field. Preliminary results indicate that the new SuRE reaction outlined in the proposal will be high yielding and easy to perform experimentally. It is also expected that it will be broad in scope, thus allowing medicinal chemists to design and make new macrocyclic peptide drug candidates with far greater freedom than is currently possible. Furthermore, as the SuRE method is expected to be equally applicable to small and large scale synthesis, it should serve as a method to scale-up (and potentially even manufacture) biologically active pharmaceutical ingredients, if any macrocyclic peptides with promising medicinal properties are identified.