Macrocycles: lessons from the distant past, recent developments, and future directions.
Macrocycles: lessons from the distant past, recent developments, and future directions.
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DOI：
10.1039/c4sc03089c
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发表时间：
2015-01-01
期刊：
影响因子：
8.4
通讯作者：
Yudin AK
中科院分区：
文献类型：
--
作者：
Yudin AK
药物靶标分子复杂性的显着增加导致对比传统小分子更大的治疗剂的需求未得到满足。药物靶标分子复杂性的显着增加导致对比传统小分子更大的治疗剂的需求未得到满足。大环化合物是由 12 个或更多原子组成的环状化合物，现在被认为是“能够胜任”研究扩展蛋白质界面的分子。然而，由于大环化合物（特别是基于肽的大环化合物）具有较大的极性表面积，因此实现细胞渗透性和生物利用度绝非易事。虽然人们可能认为这是此类化合物的致命弱点，但合成界仍在继续开发大环化合物的合成及其位点选择性修饰的创造性方法。这一观点概述了大环化合物作为一类独特分子的机械和结构问题。读者可以对一些导致当前大环化合物复兴的经典研究进行历史性的探索。此外，还尝试概述最近的发展，这些发展给大环化合物确实可能变成一种有用的治疗方式带来了希望。
A noticeable increase in molecular complexity of drug targets has created an unmet need in the therapeutic agents that are larger than traditional small molecules. A noticeable increase in molecular complexity of drug targets has created an unmet need in the therapeutic agents that are larger than traditional small molecules. Macrocycles, which are cyclic compounds comprising 12 atoms or more, are now recognized as molecules that “are up to the task” to interrogate extended protein interfaces. However, because macrocycles (particularly the ones based on peptides) are equipped with large polar surface areas, achieving cellular permeability and bioavailability is anything but straightforward. While one might consider this to be the Achilles' heel of this class of compounds, the synthetic community continues to develop creative approaches toward the synthesis of macrocycles and their site-selective modification. This perspective provides an overview of both mechanistic and structural issues that bear on macrocycles as a unique class of molecules. The reader is offered a historical foray into some of the classic studies that have resulted in the current renaissance of macrocycles. In addition, an attempt is made to overview the more recent developments that give hope that macrocycles might indeed turn into a useful therapeutic modality.