Macrocycle | EPFL Graph Search

Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples include the crown ethers, calixarenes, porphyrins, and cyclodextrins. Macrocycles describe a large, mature area of chemistry. Synthesis The formation of macrocycles by ring-closure is called macrocylization. Pioneering work was reported for studies on terpenoid macrocycles. The central challenge to macrocyclization is that ring-closing reactions do not favor the formation of large rings. Instead, small rings or polymers tend to form. This kinetic problem can be addressed by using high-dilution reactions, whereby intramolecular processes are favored relative to polymerizations. Some macrocyclizations are favored using template reactions. Templates are ions, molecules, surfaces etc. that bind and pre-organize compounds, guiding them toward formation of a particular ring size. The crown ethers are often generated in the presence of an alkali metal cation,

Multicomponent Assembly of Boronic Acid-Based Macrocycles, Cages, and Polymers

Burçak Içli

This work describes the synthesis and characterization of boronic acid-based supramolecular structures. Different reversible interactions such as boronate ester formation, imine condensation and dative B–N bond formation are used to assemble macrocycles, cages and polymers. Multicomponent condensation reactions of different diamines with tetraols and formylphenylboronic acids give macrocycles via formation of imine bonds and boronate esters. The [4+2+2] condensation products are generally preferred but larger macrocycles are observed for some combinations of staring materials. The larger macrocycles are in dynamic equilibrium with the smaller [4+2+2] products. Utilization of a triamine instead of the diamine results in the formation of molecular cages. The syntheses of these cages require the formation of 18 covalent bonds between 11 building blocks, and, interestingly, can be performed in a ball mill. Multicomponent reactions of diboronic acids, catechol derivatives, and different pyridyl ligands are described. The condensation of diboronic acids with catechols gives dioxaboroles. Upon crystallization, the ester aggregates with the N-donor ligands via dative B−N bonds. Depending on the nature of the pyridyl ligand, molecularly defined macrocycles, cages or polymeric structures are obtained. One-dimensional polymers are formed with 4,4-bipyridine and 1,2-di(4-pyridyl)ethylene, whereas a two-dimensional network is obtained with the tetradentate ligand tetra(4-pyridylphenyl)ethylene. A tripyridyl linker results in the formation trigonal prismatic cages. The size of the cages can be varied by changing the diboronic acid building block. The cages are able to encapsulate polyaromatic molecules such as triphenylene or coronene. The results highlight the potential of dative B−N bonds in structural supramolecular chemistry and crystal engineering.

EPFL2012

Generating macrocyclic inhibitors of protein-protein interactions

Gontran Sangouard

Protein-protein interactions (PPIs) play important roles in many diseases and their modulation is an attractive strategy for developing new therapeutics. However, the relatively large and often flat binding surfaces of PPIs makes the development of inhibitors based on classical small molecule drugs rather challenging. Macrocycles, a class of ring-shaped chemical structures, are able to bind to challenging targets such as PPIs, while having the potential to be cell-permeable or even orally available. The potential of targeting intracellular PPIs by macrocyclic compounds has triggered a great deal of interest in the pharmaceutical industry. A challenge with developing macrocycle-based drugs to new targets, however, is the identification of ligands, the reason for this mainly being the lack of large libraries of macrocyclic compounds that could be screened.The goal of my Ph.D. thesis project was to develop macrocyclic inhibitors for several protein-protein interactions. Towards this end, I contributed to establishing novel strategies for synthesizing and screening large macrocyclic compound libraries. Additionally, I established reported or developed new bioassays suited for the high-throughput screening of compound libraries, and I applied them for screening macrocycle libraries generated with the new methods.In my first project, I applied acoustic droplet ejection technology (ADE) for the synthesis and screening of large macrocyclic compound libraries at a picomole scale. Towards this aim, I used a synthetic strategy based on the combinatorial diversification of m bromoacetamide linear peptides with n primary amines followed by cyclization with o bis-electrophile linkers yielding m x n x o macrocycles. I used ADE to perform all liquid transfers, which proved efficient and yielded macrocycles at picomole scale. I performed the screening by directly adding assay reagents to the synthesis plates containing crude macrocycle products. As a proof-of-concept, I assembled a 2,700-member target-focused macrocycle library and screened it against the MDM2:p53 protein-protein interaction, and was able to identify macrocyclic inhibitors with micromolar to sub-micromolar affinity. Most importantly, this work validated the feasibility to synthesize combinatorial macrocycle libraries using ADE at the picomole scale, which was subsequently applied to several other approaches later developed in our lab.In my second project, I aimed at finding macrocyclic inhibitors of the PPI IL-23:IL-23R, which is an important target of several autoimmune disorders. To that end, I developed a high-throughput screening assay for identifying inhibitors of the interaction. I initially developed a screening assay based on fluorescence polarization, which turned out to be prone to artifacts. In a second attempt, I established an assay based on TR-FRET that proved reliable for the identification of IL-23:IL-23R inhibitors, and in particular also for the screening of crude products of macrocyclization reactions. I subsequently synthesized a pilot-scale library by combinatorially cyclizing 384 linear peptides with 8 cyclization linkers to generate 3,072 target-focused macrocyclic compounds. Screening the library using the TR-FRET-based assay identified single-digit micromolar inhibitors of the IL-23:IL-23R PPI, that however, were based on linear side-products of the macrocyclization reactions rather than macrocyclic structures. While no potent ma

EPFL2022

Self-assembly of organometallic macrocycles and cages

Thomas Brasey

Neutral metallamacrocycles with four or ten metal centers were obtained by reaction of [(R3P)PdCl2]2 with 2,3-dihydroxypyridine and derivatives or 2-hydroxynicotinic acid in the presence of base. In all these assemblies, the two O-donor atoms of the ligand bind to one metal center to form a chelate ring, while the N-donor atom binds to another metal center, linking the subunits together. The tetrameric complexes showed a low affinity for small aromatic diols. The procedure was adapted for the synthesis of water-soluble macrocycles: ligands which contain both the 2,3-dihydroxypyridine motive and a tertiary amine function that can be protonated were reacted in water with the acetato-bridged complex [(Et3P)Pd(CH3COO)2]2 to give tetrameric macrocycles in over 90% yields. Scrambling experiments showed that the Pd(II) macrocycles are highly inert. The reaction of ReBr3(CO)32 with 3-hydroxy-1,2,3-benzotriazine-4(3H)-one in the presence of base gave the ionic rhenium complex [ReBr(C7H4N3O2)(CO)3][NEt4], from which a neutral metallamacrocycle was obtained upon abstraction of (NEt4)Br. Its connectivity is comparable to that of the Pd(II) macrocycles. In coordinating solvents, this macrocycle disrupts and the monomeric solvent adducts are formed. In the presence of BF4-, it undergoes an anion-templated rearrangement to give a new, trimeric macrocycle which cocrystallizes with an unusual C3-symmetric [Ag(η2-benzene)3(OH2)][BF4] complex, the tetrafluoroborate anion being encapsulated in the cavity of the macrocycle. By reacting [(cymene)RuCl2]2 with 3,5-pyridinedicarboxylic acid, a trifunctional ligand in which the three donor atoms are unable to coordinate to the same metal center, an hexameric coordination cage was obtained. This complex has a trigonal antiprism geometry. Half of the carbonyl O-atoms of the bridging ligands are positioned in close proximity to each other, forming two binding sites on the surface. The cage can thus act as an exo-receptor for alkali metal cations (Na+, K+, Cs+). 1H and 13C NMR investigations as well as a single crystal X-ray analysis revealed that upon addition of alkali metal salts, the hexanuclear assembly partly rearranges to form a dodecameric coordination cage with icosahedral geometry. Although entropically disfavored, this process takes place because in this new complex all carbonyl O-atoms are part of a binding site (eight metal cations can be accommodated on the surface of the cage). Furthermore, due to the reduced surface curvature of the dodecanuclear assembly, these O-atoms are closer together, forming more suited binding sites for the alkali guest cations. To best of our knowledge, a coordination cage with an icosahedral geometry has not been reported so far.

EPFL2006