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，大环被定义为含有12个或更多原子环的任何化学物质。大环在许多科学学科中都有重要的应用，特别是与这项工作相关的是，它们在药物发现方面具有很大的潜力。这得到了超过100种已知大环药物（如抗生素红霉素）的支持，但如果不是因为大环通常很难制造这一简单事实，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，几乎都是大自然提供的，只有极少数是在实验室合成的。传统上，大环是通过在长线性分子的两个“末端”之间形成化学键来形成的，但竞争反应和副产物的形成通常占主导地位，这意味着这种过程通常效率低下。本研究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，通过称为连续环展开（SuRE）的过程，通过较小环系统的迭代扩展来“生长”大环。在SuRE中，较小的环状分子经过简单的化学转化，将线性分子附着在其上。然后，在这个新位置上加入一个反应基团来促进一种新的化学反应（或重排），这样线性分子就会把自己插入原来的环（现在它的大小增加了！）反应设计的一个关键因素是原环中存在的化学基团在放大产物中被复制，因此可以用新的连接物重复相同的一系列步骤，形成更大的环；事实上，从理论上讲，这个序列可以无限重复，从而可以制造出几乎任何大小和成分的大环。在这项工作中，将开发一种新的SuRE反应系统，用于生成具有重要医学意义的大环肽（与蛋白质化学相关）。目前，大环肽在药物化学领域引起了很大的兴趣，特别是因为它们已被证明对传统小分子药物/药物制剂治疗效果差的生物靶点有效。然而，事实上，大环肽难以使用已发表的方法（特别是大规模）制造，这是该领域进展的主要障碍。初步结果表明，本文提出的新SuRE反应产率高，易于实验。预计它的范围将很广，从而使药物化学家能够以比目前更大的自由度设计和制造新的大环肽候选药物。此外，由于SuRE方法预计同样适用于小规模和大规模合成，如果确定任何具有有前途的药用特性的大环肽，它应该作为一种扩大（甚至可能制造）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.