MacroEvoLution: A New Method for the Rapid Generation of Novel Scaffold-Diverse Macrocyclic Libraries

Abstract

Macrocycles are a structural class bearing great promise for future challenges in medicinal chemistry. Nevertheless, there are few flexible approaches for the rapid generation of structurally diverse macrocyclic compound collections. Here, an efficient method for the generation of novel macrocyclic peptide-based scaffolds is reported. The process, named here as "MacroEvoLution", is based on a cyclization screening approach that gives reliable access to novel macrocyclic architectures. Classification of building blocks into specific pools ensures that scaffolds with orthogonally addressable functionalities are generated, which can easily be used for the generation of structurally diverse compound libraries. The method grants rapid access to novel scaffolds with scalable synthesis (multi gram scale) and the introduction of further diversity at a late stage. Despite being developed for peptidic systems, the approach can easily be extended for the synthesis of systems with a decreased peptidic character.

Keywords: cyclization; diversity oriented synthesis; macrocycles; scaffold diversity; solid-phase synthesis.

Figure 1

Schematic representation of the library production: Preparation of building block pools; SPPS to generate the matrix of linear precursors, cyclization screening and selection of suitable cyclization systems, large‐scale synthesis of linear precursors and subsequent cyclization, deprotection, and final decoration.

Figure 2

Building blocks used for SPPS.

Figure 3

Selected cyclization systems representing different ring sizes (11 to 21‐membered rings) and protection group patterns.

Figure 4

Analysis of obtained ring sizes. White bar: maximum number of macrocycles of a certain ring size based on the given pool of building blocks. Gray bar: actual number of cyclization systems of a certain ring size obtained. Percentage of cyclization reached in comparison to the maximum number is given above the bars.

Figure 5

Principal moments of inertia (PMI) analysis of the MacroEvoLution library products. PMI values were computed on the minimum energy conformation for each compound and normalized PMI ratios are plotted in the triangular scatter plot. The plot shows significant shape diversity. All compounds represented in this diagram were actually synthesized.