Structure-based discovery of orally efficient inhibitors via unique interactions with H-pocket of PDE8 for the treatment of vascular dementia.

Our previous study demonstrated that phosphodiesterase 8 (PDE8) could work as a potential target for vascular dementia (VaD) using a chemical probe 3a. However, compound 3a is a chiral compound which was obtained by chiral resolution on HPLC, restricting its usage in clinic. Herein, a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors. Lead 15 exhibited potent inhibitory activity against PDE8A (IC50 = 11 nmol/L), high selectivity over other PDEs, and remarkable drug-like properties (worthy to mention is that its bioavailability was up to 100%). Oral administration of 15 significantly improved the cAMP level of the right brain and exhibited dose-dependent effects on cognitive improvement in a VaD mouse model. Notably, the X-ray crystal structure of the PDE8A-15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shaped π-π interactions with Phe785 as well as a unique H-bond network, which have never been observed in other PDE-inhibitor complex before, providing new strategies for the further rational design of novel selective inhibitors against PDE8.

High loading of Mn(ii)-metalated porphyrin in a MOF for photocatalytic CO2 reduction in gas-solid conditions.

A high loading of Mn(ii)-metalated porphyrin was achievable in a 2D porphyrin-based Mn-MOF induced by an ionic liquid. The excellent stability, sufficient redox potential, atomically dispersed porphyrin Mn(ii) sites, desired CO2 affinity, high visible light-harvesting and efficient charge separation, endow this MOF with the overall photocatalytic conversion of CO2 to CH4 in gas-solid conditions.

Comparative analysis of bacterioplankton assemblages from two subtropical karst reservoirs of southwestern China with contrasting trophic status.

Although bacterioplankton play an important role in aquatic ecosystems, less is known about bacterioplankton assemblages from subtropical karst reservoirs of southwestern China with contrasting trophic status. Here, 16S rRNA gene next-generation sequencing coupled with water chemistry analysis was applied to compare the bacterioplankton communities from a light eutrophic reservoir, DL Reservoir, and a mesotrophic reservoir, WL Reservoir, in subtropical karst area of southwestern China. Our findings indicated that Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, Cyanobacteria and Verrucomicrobia dominated bacterioplankton community with contrasting relative frequency in the two subtropical karst reservoirs. Proteobacteria and Bacteroidetes were the core communities, which played important roles in karst biogeochemical cycles. Though WT, TN and DOC play the decisive role in assembling karst aquatic bacterioplankton, trophic status exerted significantly negative direct effects on bacterioplankton community composition and alpha diversity. Due to contrasting trophic status in the two reservoirs, the dominant taxa such as Enterobacter, Clostridium sensu stricto, Candidatus Methylacidiphilum and Flavobacteriia, that harbor potential functions as valuable and natural indicators of karst water health status, differed in DL Reservoir and WL Reservoir.

Rational Design of 2-Chloroadenine Derivatives as Highly Selective Phosphodiesterase 8A Inhibitors.

To validate the hypothesis that Tyr748 is a crucial residue to aid the discovery of highly selective phosphodiesterase 8A (PDE8A) inhibitors, we identified a series of 2-chloroadenine derivatives based on the hit clofarabine. Structure-based design targeting Tyr748 in PDE8 resulted in the lead compound 3a (IC50 = 0.010 µM) with high selectivity with a reasonable druglike profile. In the X-ray crystal structure, 3a bound to PDE8A with a different mode from 3-isobutyl-1-methylxanthine (a pan-PDE inhibitor) and gave a H-bond of 2.7 Å with Tyr748, which possibly interprets the 220-fold selectivity of 3a against PDE2A. Additionally, oral administration of compound 3a achieved remarkable therapeutic effects against vascular dementia (VaD), indicating that PDE8 inhibitors could serve as potential anti-VaD agents.

Near-Infrared Phosphorescence Emission of Binuclear Mn(II) Based Metal-Organic Framework for Efficient Photoelectric Conversion.

The development of metal-organic framework (MOF) based room-temperature phosphorescence (RTP) materials has raised extensive concern owing to their widespread applications in the field of anti-counterfeiting, photovoltaics, photocatalytic reactions, and bio-imaging. Herein, one new binuclear Mn(II) based 3D MOF [Mn2(L)(BMIB)·(H2O)] (1) (H5L = 3,5-bis(3,5-dicarboxylphenxoy) benzoic acid, BMIB = tran-4-bis(2-methylimidazolyl)butylene) has been synthesized by a facile hydrothermal process. In 1, the protonated BMIB cations show infinite π-stacking arrangement, residing in the channels of the 3D network extended by L ligand and binuclear Mn(II) units. The orderly and uniform host-guest system at molecular level emits intense white light fluorescence and long-lived near infrared phosphorescence under ambient conditions. These photophysical processes were well-studied by density functional theory (DFT) calculations. Photoelectron measurements reveal high photoelectron response behavior and incident photon-to-current efficiency (IPCE).

Ionic liquid induced highly dense assembly of porphyrin in MOF nanosheets for photodynamic therapy.

Two-dimensional (2D) metal-organic framework (MOF) nanosheets have emerged as a new member of 2D nanomaterials for molecular sieving, energy conversion and storage, catalysis and biomedicine. In this paper, a highly dense assembly of porphyrin achievable in porphyrin-integrated MOF nanosheets induced by an ionic liquid is obtained by sonication exfoliation of its bulk crystals. The 2D layered structure MOF, [BMI]2[Ca3(H2TCPP)2(µ2-OH2)2(H2O)2] (1), was firstly prepared by using the ionic liquid assisted synthetic method (H6TCPP = meso-tetra(carboxyphenyl) porphyrin, BMI = 1-butyl-3-methylimidazolium). The laminated layers in 1 clearly indicate a weak interlayer non-covalent interaction but a strong metal-carboxylate bonding within the layers, which facilitates the exfoliation of 1 to form 2D MOF nanosheets (1 NSs). Powder X-ray diffraction (PXRD), high-resolution transmission electron microscopy (HR-TEM) and fast Fourier transform (FFT) patterns revealed that 1 NSs could maintain their crystalline structure after exfoliation. These MOF nanosheets exhibited excellent aqueous dispersibility, biodegradability and high cytotoxicity under light irradiation against MCF-7 cells.

The immunomodulatory role of PDEs inhibitors in immune cells: therapeutic implication in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammatory synovitis and progressive joint. Although the etiology is extremely complex, overwhelming evidence suggests that dysregulation or imbalance of the immune system plays a central role in disease pathogenesis. The bone loss and joint destruction are immunological insults mediated by infiltration and abnormal activation of various immune cells. Since pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which degrade cyclic AMP and cyclic GMP, can regulate the activity of multiple immune cells, which are considered as a potential strategy for treating RA. Therefore, this review attempted to summarize the modulating effects of PDEs on immune cells and described the molecular underpinnings and potential clinical application of PDEs inhibitors for RA.

Aqueous-phase detection of antibiotics and nitroaromatic explosives by an alkali-resistant Zn-MOF directed by an ionic liquid.

An alkali-resistant Zn-MOF directed by [BMI]Br ionic liquid, (BMI)2[Zn3(ptptc)2] (1), based on a π-electron-rich terphenyl-tetracarboxylic acid, has been synthesized under the combination of hydro/solvothermal and ionothermal condition (BMI = 1-butyl-3-methylimidazolium, H4ptptc = p-terphenyl-3,3'',5,5''-tetracarboxylic acid). In 1, the trinuclear Zn(ii) clusters are linked by the organic moieties of the ptptc ligands, resulting in a 3D anionic framework structure with highly disordered [BMI]+ cations filled in the pores. 1 exhibits good chemical stability in water and NaOH solutions (pH range of 7-12), which allow it to detect antibiotics and nitroaromatic explosives in an aquatic system. 1 represents high fluorescence quenching efficiency toward NFs (furazolidone, FZD; nitrofurazone, NZF; nitrofurantoin, NFT), NMs (ronidazole, RDZ; metronidazole, MDZ; dimetridazole, DTZ; ornidazole, ODZ) and nitrophenol (2-nitrophenol, 2-NP; 3-nitrophenol, 3-NP; 4-nitrophenol, 4-NP; 2,4,6-trinitrophenol, TNP) in water solution, respectively.

Highly Dense Packing of Chromophoric Linkers Achievable in a Pyrene-Based Metal-Organic Framework for Photoelectric Response.

Highly dense packing of chromophoric linkers is achieved in a novel pyrene-based metal-organic framework (MOF), [Zn(TBAPy)1/2(H2O)2], induced by an ionic liquid. This MOF displays a quick response to visible-light irradiation (photocurrent density of up to 4.492 µA cm-2) and is capable of repetitive on-off photocurrent switching with a large on-off ratio (37.55).

Spatial and temporal dynamics of bacterioplankton community composition in a subtropical dammed karst river of southwestern China.

River damming influences the hydro-physicochemical variations in karst water; however, such disruption in bacterioplankton communities has seldom been studied. Here, three sampling sites (city-river section, reservoir area, and outflow area) of the Ca2+ -Mg2+ -HCO3- -SO42- water type in the dammed Liu River were selected to investigate the bacterioplankton community composition as identified by high-throughput 16S rRNA gene sequencing. In the dammed Liu River, thermal regimes have been altered, which has resulted in considerable spatial-temporal differences in total dissolved solids (TDSs), oxidation-reduction potential (Eh), dissolved oxygen (DO), and pH and in a different microenvironment for bacterioplankton. Among the dominant bacterioplankton phyla, Proteobacteria, Actinobacteria, Bacteroidetes, and Cyanobacteria account for 38.99%-87.24%, 3.75%-36.55%, 4.77%-38.90%, and 0%-14.44% of the total reads (mean relative frequency), respectively. Bacterioplankton communities are dominated by Brevundimonas, Novosphingobium, Zymomonas, the Actinobacteria hgcIclade, the CL500-29 marine group, Sediminibacterium, Flavobacterium, Pseudarcicella, Cloacibacterium, and Prochlorococcus. Their abundances covary with spatial-temporal variations in hydro-physicochemical factors, as also demonstrated by beta diversity analyses. In addition, temperature plays a pivotal role in maintaining bacterioplankton biodiversity and hydro-physicochemical variations. This result also highlights the concept that ecological niches for aquatic bacteria in dammed karst rivers do not accidentally occur but are the result of a suite of environmental forces. In addition, bacterioplankton can alter the aquatic carbon/nitrogen cycle and contribute to karst river metabolism.

Design, Synthesis, and Biological Evaluation of Dual-Target Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 9A (PDE9A) for the Treatment of Alzheimer's Disease.

A series of dual-target AChE/PDE9A inhibitor compounds were designed, synthesized, and evaluated as anti-Alzheimer's Disease (AD) agents. Among these target compounds, 11a (AChE: IC50 = 0.048 µM; PDE9A: IC50 = 0.530 µM) and 11b (AChE: IC50 = 0.223 µM; PDE9A: IC50 = 0.285 µM) exhibited excellent and balanced dual-target AChE/PDE9A inhibitory activities. Meanwhile, those two compounds possess good blood-brain barrier (BBB) penetrability and low neurotoxicity. Especially, 11a and 11b could ameliorate learning deficits induced by scopolamine (Scop). Moreover, 11a could also improve cognitive and spatial memory in Aß25-35-induced cognitive deficit mice in the Morris water-maze test. In summary, our research developed a series of potential dual-target AChE/PDE9A inhibitors, and the data indicated that 11a was a promising candidate drug for the treatment of AD.

Structure-based design, synthesis, and biological evaluation of novel pyrimidinone derivatives as PDE9 inhibitors.

The pathological processes of Alzheimer's disease and type 2 diabetes mellitus have been demonstrated to be linked together. Both PDE9 inhibitors and PPARγ agonists such as rosiglitazone exhibited remarkable preclinical and clinical treatment effects for these two diseases. In this study, a series of PDE9 inhibitors combining the pharmacophore of rosiglitazone were discovered. All the compounds possessed remarkable affinities towards PDE9 and four of them have the IC50 values <5 nmol/L. In addition, these four compounds showed low cell toxicity in human SH-SY5Y neuroblastoma cells. Compound 11a, the most effective one, gave the IC50 of 1.1 nmol/L towards PDE9, which is significantly better than the reference compounds PF-04447943 and BAY 73-6691. The analysis of putative binding patterns and binding free energy of the designed compounds with PDE9 may explain the structure-activity relationships and provide evidence for further structural modifications.

Optimization of Chromeno[2,3- c]pyrrol-9(2 H)-ones as Highly Potent, Selective, and Orally Bioavailable PDE5 Inhibitors: Structure-Activity Relationship, X-ray Crystal Structure, and Pharmacodynamic Effect on Pulmonary Arterial Hypertension.

To further explore the structure-activity relationship around the chromeno[2,3- c]pyrrol-9(2 H)-one scaffold, 19 derivatives as inhibitors against PDE5 were discovered. The most potent inhibitor 3 has an IC50 of 0.32 nM with remarkable selectivity and druglike profile. Oral administration of 3 (1.25 mg/kg) caused comparable therapeutic effects to sildenafil (10.0 mg/kg) against pulmonary arterial hypertension. Further, different binding patterns from sildenafil were revealed in cocrystal structures, which provide structural templates for discovery of highly potent PDE5 inhibitors.

Discovery of novel PDE9A inhibitors with antioxidant activities for treatment of Alzheimer's disease.

Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer's disease (AD). To discover multifunctional anti-AD agents with capability of PDE9 inhibition and antioxidant activity, a series of novel pyrazolopyrimidinone derivatives, coupling with the pharmacophore of antioxidants such as ferulic and lipolic acids have been designed with the assistance of molecular docking and dynamics simulations. Twelve out of 14 synthesised compounds inhibited PDE9A with IC50 below 200 nM, and showed good antioxidant capacities in the ORAC assay. Compound 1h, the most promising multifunctional anti-AD agent, had IC50 of 56 nM against PDE9A and good antioxidant ability (ORAC (trolox) = 3.3). The selectivity of 1h over other PDEs was acceptable. In addition, 1h showed no cytotoxicity to human neuroblastoma SH-SY5Y cells. The analysis on structure-activity relationship (SAR) and binding modes of the compounds may provide insight into further modification.

Discovery of Novel Pyrazolopyrimidinone Derivatives as Phosphodiesterase 9A Inhibitors Capable of Inhibiting Butyrylcholinesterase for Treatment of Alzheimer's Disease.

Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis of Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet. In this study, a series of novel pyrazolopyrimidinone-rivastigmine hybrids were designed, synthesized, and evaluated in vitro. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds 6c and 6f showed the best IC50 values against PDE9A (6c, 14 nM; 6f, 17 nM) together with the considerable inhibition against BuChE (IC50, 6c, 3.3 µM; 6f, 0.97 µM). Their inhibitory potencies against BuChE were even higher than the anti-AD drug rivastigmine. It is worthy mentioning that both showed moderate selectivity for BuChE over acetylcholinesterase (AChE). Molecular docking studies revealed their binding patterns and explained the influence of configuration and substitutions on the inhibition of PDE9A and BuChE. Furthermore, compounds 6c and 6f exhibited negligible toxicity, which made them suitable for the further study of AD in vivo.

Discovery and Optimization of Chromeno[2,3-c]pyrrol-9(2H)-ones as Novel Selective and Orally Bioavailable Phosphodiesterase 5 Inhibitors for the Treatment of Pulmonary Arterial Hypertension.

Phosphodiesterase 5 (PDE5) inhibitors have been used as clinical agents to treat erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, we detail the discovery of a novel series of chromeno[2,3-c]pyrrol-9(2H)-one derivatives as selective and orally bioavailable inhibitors against phosphodiesterase 5. Medicinal chemistry optimization resulted in 2, which exhibits a desirable inhibitory potency of 5.6 nM with remarkable selectivity as well as excellent pharmacokinetic properties and an oral bioavailability of 63.4%. In addition, oral administration of 2 at a dose of 5.0 mg/kg caused better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate at a dose of 10.0 mg/kg. These activities along with its reasonable druglike properties, such as human liver microsomal stability, cytochrome inhibition, hERG inhibition, and pharmacological safety, indicate that 2 is a potential candidate for the treatment of PAH.

[Effects of Bisphenol A on Characteristics of Paddy Soil Microbial Community Under Different Cultural Conditions].

Bisphenol A (BPA) is widely known as a typical synthetic environmental hormone. Effects of BPA concentrations and aerations on soil microbial communities were rarely reported. This paper presented the studies on effects of various concentrations of BPA (0, 0.25 mg·kg-1, 0.50 mg·kg-1, 1.00 mg·kg-1, 2.00 mg·kg-1) and soil aertaiton (aerobic and anaerobic) on characteristics of paddy soil microbial communites by technology of qPCR (fluorescence quantitative PCR) and PCR-DGGE (polymerase chain reaction-denaturing gradient gel electrophoresis). The results lined out that: ① the microbial abundance index was significantly different among different BPA concentrations under the same condition of soil aeration (anaerobic or aerobic). However, the index of microbial evenness, Shannon-Wiener-diversity and evenness-indices were insignificantly different under these conditions. At a concentration of 0.50 mg·kg-1, the microbial abundance index reached a maximum value under anaerobic conditions; while under aerobic conditions the opposite result was found, the microbial abundance index dropped to a minimum value. ② The two-way analysis of variance (ANOVA) showed that: the concentration of BPA, soil aeration and their interaction significantly affected the abundance of bacteria, whereas the abundance of fungi was only affected by soil aeration. The study results showed that: the abundance index was a sensitive indicator for the variation of soil microbial diversity; it was a critical value for the change of soil microbial abundance when the BPA concentration was 0.50 mg·kg-1; as for the abundance of fungi, the response of bacteria abundance was more sensitive to BPA and soil aeration conditions.

[Comparison of Alarelin and Triptorelin in the long-protocol ovulation induction in in vitro fertilization and embryo transfer].

OBJECTIVE: To compare the pituitary down-regulatory effects of the two gonadotropin-releasing hormone agonists Alarelin and Triptorelin in the long protocol of ovulation induction in in vitro fertilization and embryo transfer (IVF-ET). METHODS: We included in this study 122 patients aged 24-39 years treated by IVF-ET for secondary infertility, with 10-20 pre-antral follicles and obstruction of the fallopian tube. Seventy-eight of them received Alarelin, and the other 44 Triptorelin. Comparative analyses were made on the pituitary down-regulatory effects of the two gonadotropin-releasing hormone agonists and the clinical outcomes of IVF-ET. RESULTS: No premature LH surge and ovulation, nor severe hyperovarian stimulation syndrome was found in either group. There were no significant differences between the two groups in the mean dose and duration of gonodatropin treatment, the numbers of oocytes retrieved, mature oocytes and top-quality embryos, and the rates of 2PN, multi-sperm fertilization, cleavage, embryo transfer, embryo implantation, clinical pregnancy and early miscarriage (P > 0.05), but the rate of cancelled cycles was significantly higher in the Triptorelin than in the Alarelin group (P < 0.05). CONCLUSION: Alarelin and Triptorelin can achieve similar pituitary down-regulatory effects and clinical outcomes in IVF-ET when used in the long protocol of ovulation induction.