Xinhai Zhu

Structure-Based Discovery of Highly Selective Phosphodiesterase-9A Inhibitors and Implications for Inhibitor Design

A new series of phosphodiesterase-9 (PDE9) inhibitors that contain a scaffold of 6-amino-pyrazolopyrimidinone have been discovered by a combination of structure-based design and computational docking. This procedure significantly saved the load of chemical synthesis and is an effective method for the discovery of inhibitors. The best compound 28 has an IC(50) of 21 nM and 3.3 μM, respectively, for PDE9 and PDE5 and about 3 orders of magnitude of selectivity against other PDE families. The crystal structure of the PDE9 catalytic domain in complex with 28 has been determined and shows a hydrogen bond between 28 and Tyr424. This hydrogen bond may account for the 860-fold selectivity of 28 against PDE1B, in comparison with about 30-fold selectivity of BAY73-6691. Thus, our studies suggest that Tyr424, a unique residue of PDE8 and PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors.

Discovery of a phosphodiesterase 9A inhibitor as a potential hypoglycemic agent.

Phosphodiesterase 9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of diabetes and Alzheimer’s disease. Here we report a potent PDE9 inhibitor 3r that has an IC50 of 0.6 nM and >150-fold selectivity over other PDEs. The HepG2 cell-based assay shows that 3r inhibits the mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. These activities of 3r, together with the reasonable pharmacokinetic properties and no acute toxicity at 1200 mg/kg dosage, suggest its potential as a hypoglycemic agent. The crystal structure of PDE9-3r reveals significantly different conformation and hydrogen bonding pattern of 3r from those of previously published 28s. Both 3r and 28s form a hydrogen bond with Tyr424, a unique PDE9 residue (except for PDE8), but 3r shows an additional hydrogen bond with Ala452. This structure information might be useful for design of PDE9 inhibitors.

CuI/PPh3/PEG–Water: An Efficient Catalytic System for Cross-Coupling Reaction of Aryl Iodides and Alkynes

Abstract An efficient protocol for the copper-catalyzed Sonogashira coupling of aryl iodides with terminal acetylenes in water–polyethylene glycol has been established. Both electron-rich and electron-deficient aryl iodides were arylalkynated under microwave heating or reflux in oil bath to afford good to excellent yields.

Sc(OTf)3: A Highly Efficient and Renewable Catalyst for Michael Addition of Indoles to Nitroolefins in Water

A catalytic amount of scandium trifluoromethanesulfonate [Sc(OTf)3] (2.5 mol%) was used to catalyze the Michael addition of indoles to nitroolefins in water to afford the corresponding 3-alkylated indoles in good to excellent yields. The short reaction times, excellent yields, and renewability of the catalyst are noteworthy.

Pyrrolo[2,3-c]azepine derivatives: a new class of potent protein tyrosine phosphatase 1B inhibitors.

A series of pyrrolo[2,3-c]azepine derivatives was designed, synthesized, and evaluated as a new class of inhibitors against protein tyrosine phosphatase 1B (PTP1B) in vitro. The results demonstrated that compounds bearing a biphenyl moiety were proved to markedly influence the potency of these inhibitors. Particularly, compounds 29, 35 and 36 showed interesting inhibition with IC(50) value of 16.36, 14.93 and 13.92μM, respectively.

Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor.

Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)ethyl)amino)-1-cyclopentyl-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-day]pyrimidin-4-one [(S)-C33], has an IC50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.

Whole-rainbow-color organic solid fluorophores from subtle modification of thiazolo[5,4-b]thieno[3,2-e]pyridines (TTPs)

A novel whole-rainbow-color (403 ≤ λmax ≤ 655 nm) organic solid fluorophore system was synthesised from subtle modification of a single-core structure of thiazolo[5,4-b]thieno[3,2-e]pyridines at a single site. The photoproperties and single-crystal packing structures were systematically investigated. Fifteen aggregation-induced emission luminogens (AIEgens) were obtained with a high photoluminescence efficiency (quantum yield (ΦF) as high as 63%), and 2 solid/solution dual fluorophores also were identified with ΦF greater than 20% (in tetrahydrofuran, in benzene and in the solid state). In addition, a deep-red-emissive compound (λem = 655 nm) was obtained via intermolecular self-assembly and extension of conjugation through intramolecular H-bonding.

Copper-Catalysed One-Pot Synthesis of 2,3,4,9-Tetrahydro-1H-Xanthen-1-Ones from 2-Halobenzylbromides and Cyclic-1,3-Diketones in Water

A simple, environmentally friendly, tandem C-benzylation and intramolecular O-arylation for the sequential one-pot synthesis of functionalised 4H-chromenes is reported. The reactions between 2-halobenzylbromides and cyclic-1,3-diketones were catalysed by CuO/oxalohydrazide/hexane-2,5-dione in water to produce 2,3,4,9-tetrahydro-1H-xanthen-1-ones in moderate to high yields.Graphical AbstractA simple, environmental friendly, tandem C-benzylation and intramolecular O-arylation for the sequential one-pot synthesis of 2,3,4,9-tetrahydro-1H-xanthen-1-ones in water is described.

GRGDS-functionalized chitosan nanoparticles as a potential intravenous hemostat for traumatic hemorrhage control in an animal model

Hemostats, which are used for immediate intervention during internal hemorrhage in order to reduce resulting mortality and morbidity, are relatively rare. Here, we describe novel intravenous nanoparticles (CPG-NPs-2000) with chitosan succinate (CSS) as cores, polyethylene glycol (PEG-2000) as spacers and a glycine-arginine-glycine-aspartic acid-serine (GRGDS) peptide as targeted, active hemostatic motifs. CPG-NPs-2000 displayed significant hemostatic efficacy, compared to the saline control, CSS nanoparticles, and tranexamic acid in liver trauma rat models. Further studies have demonstrated that CPG-NPs-2000 are effectively cleared from organs and blood, within 2 and 48 h, respectively. In addition, administration of CPG-NPs-2000 does not affect clotting function under normal physiological conditions, indicating their potential safety in vivo. CPG-NPs-2000 exhibit excellent thermal stability, good solubility, and redistribution ability, in addition to being low cost. These characteristics indicate that CPG-NPs-2000 may have strong potential as effective intravenous hemostats for treating severe internal bleeding.