Synthesis of compounds based on a dimesitylmethane scaffold and representative binding studies showing di- vs monosaccharide preference

Koch, Niklas; Rosien, Jan-Ruven; Mazik, Monika

doi:10.1016/j.tet.2014.09.016

Cited by 25 publications

(7 citation statements)

References 69 publications

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“…For α‐Man, the largest Δ δ occurred with the peak corresponding to H 7’ , with Δ δ =0.66 ppm upfield, and the second‐largest shift was for the peak corresponding to H 1 , with Δ δ =0.59 ppm upfield. When involved in C−H⋅⋅⋅π interactions with aryl rings of SCRs, protons shift upfield, [21c,31,32i,j,33a–i,34a,43b–o] suggesting the formation of C−H⋅⋅⋅π interactions between these protons and with the aromatic rings of SCR032 . 1 H NMR of the indole‐based SCRs in all the titrations presented significant downfield shifts.…”

Section: Resultsmentioning

confidence: 99%

Regiochemical Effects on the Carbohydrate Binding and Selectivity of Flexible Synthetic Carbohydrate Receptors with Indole and Quinoline Heterocyclic Groups

et al. 2021

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Synthetic carbohydrate receptors (SCRs) that bind cell‐surface carbohydrates could be used for disease detection, drug‐delivery, and therapeutics, or for the site‐selective modification of complex carbohydrates, but their potential has not been realized because of remaining challenges associated with binding affinity and substrate selectivity. We have reported recently a series of flexible SCRs based upon a biaryl core with four pendant heterocyclic groups that bind glycans selectively through noncovalent interactions. Here we continue to explore the role of heterocycles on substrate selectivity by expanding our library to include a series of indole and quinoline heterocycles that vary in their regiochemistry of attachment to the biaryl core. The binding of these SCRs to a series of biologically‐relevant carbohydrates was studied by 1H NMR titrations in CD2Cl2 and density‐functional theory calculations. We find SCR030, SCR034 and SCR037 are selective, SCR031, SCR032, and SCR039 are strong binders, and SCR033, SCR035, SCR036, and SCR038 are promiscuous and bind weakly. Computational analysis reveals the importance of C−H⋅⋅⋅π and H‐bonding interactions in defining the binding properties of these new receptors. By combining these data with those obtained from our previous studies on this class of flexible SCRs, we develop a series of design rules that account for the binding of all SCRs of this class, and anticipate the binding of future, not‐yet imagined tetrapodal SCRs.

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Section: Resultsmentioning

confidence: 99%

Regiochemical Effects on the Carbohydrate Binding and Selectivity of Flexible Synthetic Carbohydrate Receptors with Indole and Quinoline Heterocyclic Groups

et al. 2021

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“…Subsequent geometry optimization using a force field helped to confirm and visualize the interactions that led to the reported selectivity. Similar examples can be found in the work of Mazik, ,,,,,,,,,,,,,,,− ,− Roelens, ,,,,,− , and Davis. ,,,,,,,,,− These examples, however, strongly rely on chemical intuition to guess the placement of the guest inside the rigid cage, followed by a local conformational search and geometry optimization. Flexible SCRs constitute a further challenge for theoretical methods because a structural search must screen a much larger conformational space to localize and validate the structure of the complex.…”

Section: Structure–activity Relationships Of Flexible Scrs Unveiled B...mentioning

confidence: 68%

Flexible Synthetic Carbohydrate Receptors as Inhibitors of Viral Attachment

et al. 2020

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Carbohydrate–receptor interactions are often involved in the docking of viruses to host cells, and this docking is a necessary step in the virus life cycle that precedes infection and, ultimately, replication. Despite the conserved structures of the glycans involved in docking, they are still considered “undruggable”, meaning these glycans are beyond the scope of conventional pharmacological strategies. Recent advances in the development of synthetic carbohydrate receptors (SCRs), small molecules that bind carbohydrates, could bring carbohydrate–receptor interactions within the purview of druggable targets. Here we discuss the role of carbohydrate–receptor interactions in viral infection, the evolution of SCRs, and recent results demonstrating their ability to prevent viral infections in vitro. Common SCR design strategies based on boronic ester formation, metal chelation, and noncovalent interactions are discussed. The benefits of incorporating the idiosyncrasies of natural glycan-binding proteinsincluding flexibility, cooperativity, and multivalencyinto SCR design to achieve nonglucosidic specificity are shown. These studies into SCR design and binding could lead to new strategies for mitigating the grave threat to human health posed by enveloped viruses, which are heavily glycosylated viroids that are the cause of some of the most pressing and untreatable diseases, including HIV, Dengue, Zika, influenza, and SARS-CoV-2.

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“…As a part of our program aimed at the development of selective and effective carbohydrate receptors − we have recently designed and reported receptor systems of types I and II shown in Figure . The macrocyclic compounds 1 – 5 and the acyclic molecules 6 – 9 , consisting of two central triethylbenzene units, were prepared as first representatives of the two groups.…”

Section: Introductionmentioning

confidence: 99%

Carbohydrate Receptors Combining Both a Macrocyclic Building Block and Flexible Side Arms as Recognition Units: Design, Syntheses, and Binding Studies

Lippe

Mazik

2015

J. Org. Chem.

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Carbohydrate receptors combining a macrocyclic building block and two flexible side arms were designed on the base of the analysis of the binding motifs found in the crystal structures of the complexes formed between artificial receptors and monosaccharides, reported previously by our group. Binding studies in two-phase systems, such as extractions of sugars from water into organic phase, as well as in homogeneous organic media, using (1)H NMR and fluorescence spectroscopic titrations, confirmed the suitability of the designed compounds to act as highly effective and selective carbohydrate receptors. Depending on the nature of the bridges and side arms used as the building blocks, various receptors with different binding properties could be developed. The obtained results confirmed the validity of the receptor design and revealed that crystalline receptor-sugar complexes are particularly a valuable basis for the design of new effective receptor systems.

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Synthesis of compounds based on a dimesitylmethane scaffold and representative binding studies showing di- vs monosaccharide preference

Cited by 25 publications

References 69 publications

Regiochemical Effects on the Carbohydrate Binding and Selectivity of Flexible Synthetic Carbohydrate Receptors with Indole and Quinoline Heterocyclic Groups

Regiochemical Effects on the Carbohydrate Binding and Selectivity of Flexible Synthetic Carbohydrate Receptors with Indole and Quinoline Heterocyclic Groups

Flexible Synthetic Carbohydrate Receptors as Inhibitors of Viral Attachment

Carbohydrate Receptors Combining Both a Macrocyclic Building Block and Flexible Side Arms as Recognition Units: Design, Syntheses, and Binding Studies

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