Abstract
The identification of new bioactive small molecules is increasingly reliant upon the
synthesis and screening of chemical libraries. The extent of structural diversity
and the proportion of unique scaffolds in a library are commonly acknowledged to be
the most important factors in determining its success in identifying new biologically
relevant compounds. Particularly important in this respect are macrocycles, which
display unique physicochemical attributes and are used in many clinical applications.
Despite these advantages, macrocycles remain under-represented in many contemporary
screening collections, predominantly due to their synthetic intractability. Diversity-oriented
synthesis is a powerful method for the construction of deliberately diverse collections
of small molecules, and many research groups are working to apply its principles to
the synthesis of structurally and functionally diverse macrocyclic libraries. In this
short review we introduce why macrocycles are promising chemotypes in screening libraries,
especially for challenging biological targets such as protein–protein interactions,
and we review a collection of strategies developed in our laboratory for the diversity-oriented
synthesis of macrocycle libraries. We analyse a selection of the macrocycle collections
generated using these approaches and conclude with our perspective on future directions
of the field.
1 Introduction
1.1 Chemical Libraries in Drug Discovery and Chemical Biology
1.2 Macrocycles in Screening Collections
1.3 Diversity-Oriented Synthesis
2 Build/Couple/Pair
2.1 Strategy Overview
2.2 Typical B/C/P Strategies
2.3 Advanced B/C/P Strategies
2.4 Two-Directional Synthesis
3 Alternative Approaches to Macrocycle Library Synthesis
4 Discussion and Concluding Remarks
Key words
diversity-oriented synthesis - diversity - macrocycles - small molecule libraries
- cheminformatics
