No abstract

A monoselective synthesis of aryl-C-Δ(1,2)-glycosides from 1-iodoglycals via palladium-catalyzed ortho-C-H activation of N-quinolyl benzamides has been developed. An amino acid derivative was used as a crucial ligand to improve the yield and monoselectivity of the coupling reaction. The utility of this protocol was demonstrated by a concise synthesis of key moieties of some natural products.

Rhizoma Dioscoreae septemlobae (RDSE) has been widely used for the treatment of hyperuricemia in China. However, the therapeutic mechanism has been unknown. This study investigated the antihyperuricemic mechanisms of the extracts obtained from RDSE and its main component dioscin (DIS) in hyperuricemic mice. Hyperuricemic mice were induced by potassium oxonate (250 mg/kg). RDSE or DIS was orally administered to hyperuricemic mice at dosages of 319.22, 638.43, 1276.86 mg/kg/day for 10 days, respectively. Uric acid or creatinine in serum and urine was determined by HPLC or HPLC-MS/MS, respectively. The xanthine oxidase (XO) activities in mice liver were examined in vitro. Protein levels of organic anion transporter 1 (mOAT1), urate transporter 1 (mURAT1) and organic cation transporter 2 (mOCT2) in the kidney were analyzed by western blotting. The results indicated that uric acid and creatinine in serum were significantly increased by potassium oxonate, as compared to that of control mice. Compared saline-treated group, after RDSE treatment in the high and middle dose, the expression of mOAT1 increased 47.98 and 54.48 %, respectively, which accompanied with the decreased expression of mURAT1 (47.63 %) in high dose. After DIS treatment in high, middle and low dose, the expression of mOAT1 increased 23.93, 32.80 and 25.28 % compared to saline-treated group, respectively, which accompanied with the decreased expression of mURAT1 (51.07, 51.42 and 51.35 %). However, RDSE and DIS displayed a weak XO inhibition activity compared with allopurinol. Therefore, RDSE and DIS processed uricosuric and nephroprotective actions by regulation of mOAT1, mURAT1 and mOCT2.

No abstract

De novo macrocyclic peptides, derived using selection technologies such as phage and mRNA display, present unique and unexpected solutions to challenging biological problems. This is due in part to their unusual folds, which are able to present side chains in ways not available to canonical structures such as α-helices and β-sheets. Despite much recent interest in these molecules, their folding and binding behavior remains poorly characterized. In this work, we present cocrystallization, docking, and solution NMR structures of three de novo macrocyclic peptides that all bind as competitive inhibitors with single-digit nanomolar K i to the active site of human pancreatic α-amylase. We show that a short stably folded motif in one of these is nucleated by internal hydrophobic interactions in an otherwise dynamic conformation in solution. Comparison of the solution structures with a target-bound structure from docking indicates that stabilization of the bound conformation is provided through interactions with the target protein after binding. These three structures also reveal a surprising functional convergence to present a motif of a single arginine sandwiched between two aromatic residues in the interactions of the peptide with the key catalytic residues of the enzyme, despite little to no other structural homology. Our results suggest that intramolecular hydrophobic interactions are important for priming binding of small macrocyclic peptides to their target and that high rigidity is not necessary for high affinity.