Distortion of the Large Cages Encapsulating Cyclic Molecules and Empty Small Cages of Structure II Clathrate Hydrates

Understandings of structure-based properties of porous materials, such as gas storage and gas separation performance, are important. Here, the crystal structures of the canonical structure II (sII) clathrate hydrates encapsulating cyclic molecules (tetrahydrofuran, cyclopentane, furan, and tetrahydropyran) are studied. To understand the effect of guest molecules on the host water framework, we performed powder X-ray diffraction measurements where the hydrate structures and guest distribution within 5¹²6⁴ cages were obtained by the direct-space technique followed by the Rietveld refinement. It was shown that the sizes of the 5¹² and 5¹²6⁴ cages of sII hydrates expand, as its unit-cell size is enlarged by the guest. In this process, it is revealed that the shape of 5¹²6⁴ cages with larger guest molecules became more spherical and volume ratio of empty small 5¹² cages in the unit cell decreases. Our findings from crystallographic point of view may give insights into better understanding of the thermodynamic stability and higher gas storage capacity of binary clathrate hydrates

Identification of Adenine and Benzimidazole Nucleosides as Potent Human Concentrative Nucleoside Transporter 2 Inhibitors: Potential Treatment for Hyperuricemia and Gout

To test the hypothesis that inhibitors of human concentrative nucleoside transporter 2 (hCNT2) suppress increases in serum urate levels derived from dietary purines, we previously identified adenosine derivative <b>1</b> as a potent hCNT2 inhibitor (IC₅₀ = 0.64 μM), but further study was hampered due to its poor solubility. Here we describe the results of subsequent research to identify more soluble and more potent hCNT2 inhibitors, leading to the discovery of the benzimidazole nucleoside <b>22</b>, which is the most potent hCNT2 inhibitor (IC₅₀ = 0.062 μM) reported to date. Compound <b>22</b> significantly suppressed the increase in plasma uric acid levels after oral administration of purine nucleosides in rats. Because compound <b>22</b> was poorly absorbed orally in rats (<i>F</i> = 0.51%), its pharmacologic action was mostly limited to the gastrointestinal tract. These findings suggest that inhibition of hCNT2 in the gastrointestinal tract can be a promising approach for the treatment of hyperuricemia

Identification of Adenine and Benzimidazole Nucleosides as Potent Human Concentrative Nucleoside Transporter 2 Inhibitors: Potential Treatment for Hyperuricemia and Gout

To test the hypothesis that inhibitors of human concentrative nucleoside transporter 2 (hCNT2) suppress increases in serum urate levels derived from dietary purines, we previously identified adenosine derivative <b>1</b> as a potent hCNT2 inhibitor (IC₅₀ = 0.64 μM), but further study was hampered due to its poor solubility. Here we describe the results of subsequent research to identify more soluble and more potent hCNT2 inhibitors, leading to the discovery of the benzimidazole nucleoside <b>22</b>, which is the most potent hCNT2 inhibitor (IC₅₀ = 0.062 μM) reported to date. Compound <b>22</b> significantly suppressed the increase in plasma uric acid levels after oral administration of purine nucleosides in rats. Because compound <b>22</b> was poorly absorbed orally in rats (<i>F</i> = 0.51%), its pharmacologic action was mostly limited to the gastrointestinal tract. These findings suggest that inhibition of hCNT2 in the gastrointestinal tract can be a promising approach for the treatment of hyperuricemia