A diversity-oriented synthesis strategy enabling the combinatorial-type variation of macrocyclic peptidomimetic scaffolds.

Albert Isidro-Llobet,David R Spring,Gabriela Méndez-Abt,Mette R Hansen,Elisa Giacomini,Warren R J D Galloway,Laura Carro,Hannah F Sore,Yaw Sing Tan,Kathy Hadje Georgiou

doi:10.1039/c5ob00371g

Abstract

Macrocyclic peptidomimetics are associated with a broad range of biological activities. However, despite such potentially valuable properties, the macrocyclic peptidomimetic structural class is generally considered as being poorly explored within drug discovery. This has been attributed to the lack of general methods for producing collections of macrocyclic peptidomimetics with high levels of structural, and thus shape, diversity. In particular, there is a lack of scaffold diversity in current macrocyclic peptidomimetic libraries; indeed, the efficient construction of diverse molecular scaffolds presents a formidable general challenge to the synthetic chemist. Herein we describe a new, advanced strategy for the diversity-oriented synthesis (DOS) of macrocyclic peptidomimetics that enables the combinatorial variation of molecular scaffolds (core macrocyclic ring architectures). The generality and robustness of this DOS strategy is demonstrated by the step-efficient synthesis of a structurally diverse library of over 200 macrocyclic peptidomimetic compounds, each based around a distinct molecular scaffold and isolated in milligram quantities, from readily available building-blocks. To the best of our knowledge this represents an unprecedented level of scaffold diversity in a synthetically derived library of macrocyclic peptidomimetics. Cheminformatic analysis indicated that the library compounds access regions of chemical space that are distinct from those addressed by top-selling brand-name drugs and macrocyclic natural products, illustrating the value of our DOS approach to sample regions of chemical space underexploited in current drug discovery efforts. An analysis of three-dimensional molecular shapes illustrated that the DOS library has a relatively high level of shape diversity.

Highlights

Macrocycles are ring structures of 12 or more atoms
The generality and robustness of this diversityoriented synthesis (DOS) strategy is demonstrated by the step-efficient synthesis of a structurally diverse library of over 200 macrocyclic peptidomimetic compounds, each based around a distinct molecular scaffold and isolated in milligram quantities, from readily available building-blocks
Our advanced DOS strategy towards diverse macrocyclic peptidomimetic scaffolds was based around the use of three general types of chiral building blocks of the synthesis: “azido amines” (“initiating” building blocks), “Boc-amino-acids” (“propagating” building blocks) and “alkyne-acids” (“capping” building blocks, Scheme 1).[38]

Summary

Introduction

Macrocycles are ring structures of 12 or more atoms. Where present in a small molecule, the macrocyclic ring architecture typically serves as the molecular scaffold; that is, the core rigidifying structural feature of a molecule that has the largest influence upon how it presents its chemical information (i.e. functional groups and potential binding regions) in three dimensions (3D).[1,2,3,4] Macrocyclic peptidomimetics are a subclass of macrocycles, designed to act as functional substitutes for peptide motifs or proteins, whilst having more desirable biological properties.[4,5] For example, this can involve the 4570 | Org. The generality and robustness of this DOS strategy is demonstrated by the step-efficient synthesis of a structurally diverse library of over 200 macrocyclic peptidomimetic compounds, each based around a distinct molecular scaffold and isolated in milligram quantities, from readily available building-blocks.

Results

Conclusion