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Expanding the Repertoire of Low-Molecular-Weight Pentafluorosulfanyl-Substituted Scaffolds.

ABSTRACT: The pentafluorosulfanyl (-SF₅ ) functional group is of increasing interest as a bioisostere in medicinal chemistry. A library of SF₅ -containing compounds, including amide, isoxazole, and oxindole derivatives, was synthesised using a range of solution-based and solventless methods, including microwave and ball-mill techniques. The library was tested against targets including human dihydroorotate dehydrogenase (HDHODH). A subsequent focused approach led to synthesis of analogues of the clinically used disease modifying anti-rheumatic drugs (DMARDs), Teriflunomide and Leflunomide, considered for potential COVID-19 use, where SF₅ bioisostere deployment led to improved inhibition of HDHODH compared with the parent drugs. The results demonstrate the utility of the SF₅ group in medicinal chemistry.

SUBMITTER: Jose A

PROVIDER: S-EPMC9305131 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Expanding the Repertoire of Low-Molecular-Weight Pentafluorosulfanyl-Substituted Scaffolds.

Jose Arathy A Guest Daniel D LeGay Remi R Tizzard Graham J GJ Coles Simon J SJ Derveni Mariliza M Wright Edward E Marrison Lester L Lee Alpha A AA Morris Aaron A Robinson Matt M von Delft Frank F Fearon Daren D Koekemoer Lizbé L Matviuk Tetiana T Aimon Anthony A Schofield Christopher J CJ Malla Tika R TR London Nir N Greenland Barnaby W BW Bagley Mark C MC Spencer John J The Covid Moonshot Consortium

ChemMedChem 20220222 7

The pentafluorosulfanyl (-SF<sub>5</sub> ) functional group is of increasing interest as a bioisostere in medicinal chemistry. A library of SF<sub>5</sub> -containing compounds, including amide, isoxazole, and oxindole derivatives, was synthesised using a range of solution-based and solventless methods, including microwave and ball-mill techniques. The library was tested against targets including human dihydroorotate dehydrogenase (HDHODH). A subsequent focused approach led to synthesis of analo ...[more]

PMID: 35191598

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Project description:While hyaluronic acid (HA)-based hydrogels have been used clinically for decades, the mechanisms by which HA exerts molecular weight-dependent bioactivity and how chemical modification and crosslinking may affect molecular weight-dependent bioactivity remain poorly understood. This knowledge gap presents a significant barrier to designing HA hydrogels with predictable bioactivities. As HA has been widely reported to have molecular weight-dependent effects on endothelial cells (ECs), we investigated how the molecular weight of HA in either soluble or crosslinked forms affects angiogenesis and interrogated CD44 clustering on the surface of endothelial cells as a candidate mechanism for these affects. Using soluble HA, our results show high molecular weight (HMW) HA, but not low molecular weight (LMW) HA, increased viability and tube formation in cultured human cerebral microvascular ECs (HCMVECs). No size of HA affected proliferation. When HCMVECs were cultured with crosslinked HA of varying molecular weights in the form of HA-based microporous annealed particle scaffold (HMAPS), the cell response was comparable to when cultured with soluble HA. Similarly, when implanted subcutaneously, HMAPS with HMW HA were more vascularized than those with LMW HA. We also show that antibody-mediated CD44 clustering resulted in HCMVECs with increased viability and tube-like structure formation in a manner comparable to exposure to HMW HA, suggesting that HMW acts through CD44 clustering. STATEMENT OF SIGNIFICANCE: Biomaterials based on hyaluronic acid (HA), a bioactive extracellular matrix polysaccharide, have been used in clinical products for several years. Despite the knowledge that HA molecular weight heavily influences its bioactivity, molecular weight has been largely ignored in the development of HA-based biomaterials. Given the high viscosity of high molecular weight HA typically found in native tissues, lower molecular weight polysaccharides have been used most commonly for biomaterial fabrication. By comparing the ability of injectable, microporous annealed particle scaffolds (MAPS) fabricated from variably sized HA to promote angiogenesis, this study demonstrates that MAPS with high molecular weight HA better support vascularization, likely through an unique ability to induce clustering of CD44 receptors on endothelial cells.

Dataset Information

Expanding the Repertoire of Low-Molecular-Weight Pentafluorosulfanyl-Substituted Scaffolds.

Publications

Expanding the Repertoire of Low-Molecular-Weight Pentafluorosulfanyl-Substituted Scaffolds.

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