Practical Medicinal Chemistry with Macrocycles – Design, Synthesis, and Case Studies

Chapter 5 by Scott Lokey and Andrew Bockus

Introduction

Cyclic peptide natural products and their synthetic mimics have gained prominence as potential sources of next‐generation therapeutics and biological probes [1–4]. The size and structural complexity of these compounds sets them apart from common synthetic drugs, allowing them to access the “undruggable” target space beyond enzymatic active sites and receptor binding pockets to include activities against a variety of nontraditional targets [4]. Although cyclic peptides have molecular weights and polar group counts that exceed the typical parameters for “drug‐likeness” [5, 6], many are capable of penetrating cells by passive diffusion, and some, such as cyclosporin A, are orally bioavailable [7]. Passive diffusion offers an advantage over other forms of permeation such as paracellular transport, carrier‐mediated transport, and active non‐receptor‐mediated uptake (e.g., micropinocytosis) because the ability to cross the membrane is dictated by the intrinsic properties of the molecule (e.g., molecular weight, number of intramolecular hydrogen bonds (IMHBs), polar surface area, flexibility, lipophilicity) rather than those of the target tissue or cellular physiology (e.g., size of tight junctions, type of transport proteins, invagination of the membrane in response to surface assemblies). Thus, these natural products may provide insights into the requirements for optimizing the ADME properties of large macrocycles.
Further, the stereochemical and conformational complexity of cyclic peptides serves as a model for the design of synthetic scaffolds capable of modulating challenging biological targets such as protein–protein interactions and allosteric binding sites in both extracellular and intracellular space [8–13]. Despite this potential, few efforts have been made to systematically assess the relationship between the structure, pharmacokinetics, and bioactivity of cyclic peptide natural products. This is due in part to the limited number of known passively permeable cyclic peptide and cyclic peptide/polyketide natural products. Therefore the generality of cyclic peptides as orally bioavailable bioactive scaffolds remains an open question.
The few studies that have systematically explored the relationships between structure and permeability in cyclic peptides have been limited to a small subset of methylated (1) [14] and non‐methylated (2) [15] cyclic hexapeptide scaffolds that bear resemblance to baceridin (3) [16], segelin I (4) [17], and the nocardiamide (5/6) [18] cyclic hexapeptide natural products (Figure 5.1 and Chapter 3) [19–22].
The work of Lokey and Jacobson [23–27], Fairlie and Craik [28–30], and others has begun to elucidate the structure– permeability relationships of more complex natural products, but the vast majority of these studies have been limited to cyclic penta‐ and hexapeptides with no observed bioactivity. Thus, the new frontier in understanding structure–permeability relationships in cyclic peptides has moved to the chemical space that encompasses macrocycles of higher molecular weight [31, 32], greater structural complexity, and significant bioactivity.
Here, we first discuss the two‐dimensional and three dimensional (3D) structures of known passively permeable cyclic peptide natural products and then highlight recently discovered cyclic peptide natural products with notable bioactivity that could serve as starting structures
for future systematic structural studies to optimize oral absorption.

October 2017
Wiley Publishers

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Discovery of potent and orally bioavailable macrocyclic peptide-peptoid hybrid CXCR7 modulators.