title: A diversity-oriented synthesis strategy enabling the combinatorial-type variation of macrocyclic peptidomimetic scaffolds.
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.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK. spring@ch.cam.ac.uk.
authors.forename: Albert
authors.initials: A
authors.lastname: Isidro-Llobet
authors.forename: Kathy
authors.initials: K
authors.lastname: Hadje Georgiou
authors.forename: Warren R J D
authors.initials: WR
authors.lastname: Galloway
authors.forename: Elisa
authors.initials: E
authors.lastname: Giacomini
authors.forename: Mette R
authors.initials: MR
authors.lastname: Hansen
authors.forename: Gabriela
authors.initials: G
authors.lastname: Méndez-Abt
authors.forename: Yaw Sing
authors.initials: YS
authors.lastname: Tan
authors.forename: Laura
authors.initials: L
authors.lastname: Carro
authors.forename: Hannah F
authors.initials: HF
authors.lastname: Sore
authors.forename: David R
authors.initials: DR
authors.lastname: Spring
mesh_terms: D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D047028:Macrocyclic Compounds; D057786:Peptidomimetics; D054852:Small Molecule Libraries