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Abstract: In this paper, we apply the maximum principle and the theory of compensated compactness to establish an existence theorem for global weak solutions to the Cauchy problem of the non-strictly hyperbolic system—a special system of Euler equation with a general source term. [Copyright &y& Elsevier]

A new acetylenic ketone isolated from the bark of Litsea rotundifolia var. oblongifolia has been characterized as 13-tetradecyn-2-one on the basis of detailed spectroscopic analysis and comparison with related model compounds. Four known related lipids have also been isolated from this plant. [ABSTRACT FROM AUTHOR]

This new highly efficient method for the deprotection of imidazoles, benzimidazoles, and pyrazoles is presented using aliphatic C1-C4 alcohols and trimethylamine at room temperature. [ABSTRACT FROM AUTHOR]

Rationale: Currently available PDE2 inhibitors have poor brain penetration that limits their therapeutic utility in the treatment of depression. Hcyb1 is a novel selective PDE2 inhibitor that was introduced more lipophilic groups with polar functionality to the scaffold pyrazolopyrimidinone to improve the blood-brain barrier (BBB) penetration. Our previous study suggested that Hcyb1 increased the neuronal cell viability and exhibited antidepressant-like effects, which were parallel to the currently available PDE2 inhibitor Bay 60-7550. Objectives: The present study investigated whether Hcyb1 protected HT-22 cells against corticosterone-induced neurotoxicity and produced antidepressant-like effects in behavioral tests in stressed mice. Methods: The neuroprotective effects of Hcyb1 against corticosterone-induced cell lesion were examined by cell viability (MTS) assay. The enzyme-linked immunosorbent assay (ELISA) and immunoblot analysis were used to determine the levels of cAMP or cGMP and expression of pCREB or BDNF, respectively, in the corticosterone-treated HT-22 cells. The antidepressant-like effects of Hcyb1 were determined in the tail suspension and novelty suppressed feeding tests in stressed mice. Results: In the cell-based assay, Hcyb1 significantly increased cell viability of HT-22 cells against corticosterone-induced neurotoxicity in a time- and dose-dependent manner. Hcyb1 also rescued corticosterone-induced decreases in both cGMP and cAMP levels, pCREB/CREB and BDNF expression. These protective effects of Hcyb1 were prevented by pretreatment with either the PKA inhibitor H89 or the PKG inhibitor KT5823. Moreover, Hcyb1 reversed acute stress–induced increases in immobility time and the latency to feed in the tail suspension and novelty suppressed feeding tests, respectively, which were prevented by pretreatment with H89 or KT5823. Conclusion: These findings provide evidence that the neuroprotective effects of Hcyb1 are mediated by PDE2-dependent cAMP/cGMP signaling. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders. Herein, based on the existing PDE2 inhibitors and their binding modes, a series of purin-6-one derivatives were designed, synthesized and evaluated for PDE2 inhibitory activities, which led to the discovery of the best compounds 6p and 6s with significant inhibitory potency (IC 50 : 72 and 81 nM, respectively). Docking simulation was performed to insert compound 6s into the crystal structure of PDE2 at the active site to determine the binding mode. Furthermore, compound 6s significantly protected HT-22 cells against corticosterone-induced cytotoxicity and rescued corticosterone-induced decreases in cAMP and cGMP levels. It also produced anxiolytic-like effect in the elevated plus-maze test and exhibited favorable pharmacokinetic properties in vivo. These results might bring significant instruction for further development of potent PDE2 inhibitors. [ABSTRACT FROM AUTHOR]

Summary: Background: Major depressive disorder (MDD) is a mental disease characterized by depressed mood, lifetime anxiety, and deficits of learning and memory. Inhibition of phosphodiesterase 9 (PDE9) has been reported to improve rodent cognitive and memory function. However, the role of PDE9 in MDD, in particular its manifestations of depression and anxiety, has not been investigated. Methods: We examined the protective effects of WYQ‐C36D (C36D), a novel PDE9 inhibitor, against corticosterone‐induced cytotoxicity, pCREB/CREB and BDNF expression by cell viability, and immunoblot assays in HT‐22 cells. The potential effects of C36D at doses of 0.1, 0.5, and 1 mg/kg on stress‐induced depression‐ and anxiety‐like behaviors and memory deficits were also examined in mice. Results: C36D significantly protected HT‐22 cells against corticosterone‐induced cytotoxicity and rescued corticosterone‐induced decreases in cGMP, CREB phosphorylation, and BDNF expression. All these effects were otherwise blocked by the PKG inhibitor Rp‐8‐Br‐PET‐cGMPS (Rp8). In addition, when tested in vivo in stressed mice, C36D produced antidepressant‐like effects on behavior, as shown by decreased immobility time both in the forced swimming and tail suspension tests. C36D also showed anxiolytic‐like and memory‐enhancing effects in the elevated plus‐maze and novel object recognition tests. Conclusion: Our results show that inhibition of PDE9 by C36D produces antidepressant‐ and anxiolytic‐like behavioral effects and memory enhancement by activating cGMP/PKG signaling pathway. PDE9 inhibitors may have the potential as a novel class of drug to treat MDD. [ABSTRACT FROM AUTHOR]

Summary: Aims: Depression is currently the most common mood disorder. Regulation of intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) signaling by phosphodiesterase (PDE) inhibition has been paid much attention for treatment of depression. This study aimed to investigate the neuroprotective effects of Hcyb1, a novel PDE2 inhibitor, in HT‐22 cells and antidepressant‐like effects in mouse models of depression. Methods: Hcyb1 was synthesized and its selectivity upon PDE2 was tested. Moreover, HT‐22 hippocampal cells were used to determine the effects of Hcyb1 on cell viability, cyclic nucleotide levels, and the downstream molecules related to cAMP/cGMP signaling by neurochemical, enzyme‐linked immunosorbent, and immunoblot assays in vitro. The antidepressant‐like effects of Hcyb1 were also determined in the forced swimming and tail suspension tests in mice. Results: Hcyb1 had a highly selective inhibition of PDE2A (IC50 = 0.57 ± 0.03 μmol/L) and over 250‐fold selectivity against other recombinant PDE family members. Hcyb1 at concentrations of 10−10 and 10−9 mol/L significantly increased cell viability after treatment for 24 hours. At concentrations of 10−9~10−7 mol/L, Hcyb1 also increased cGMP levels by 1.7~2.3 folds after 10‐minute treatment. Furthermore, Hcyb1 at the concentrations of 10−9 mol/L increased both cGMP and cAMP levels 24 hours after treatment. The levels of phosphorylation of CREB and BDNF were also increased by Hcyb1 treatment in HT‐22 cells for 24 hours. Finally, in the in vivo tests, Hcyb1 (0.5, 1, and 2 mg/kg, i.g.) decreased the immobility time in both forced swimming and tail suspension tests, without altering locomotor activity. Conclusion: These results suggest that the novel PDE2 inhibitor Hcyb1 produced neuroprotective and antidepressant‐like effects most likely mediated by cAMP/cGMP‐CREB‐BDNF signaling. [ABSTRACT FROM AUTHOR]

The cocrystallization of lomefloxacin (Lf) with barbituric acid (HBA) and/or isophthalic acid (H2ip) leads to novel binary and ternary salts via hydrogen-bonding recognition. X-ray single-crystal diffraction analyses show that zwitterionic lomefloxacin can adjust itself to fulfill a different supramolecular array in either binary salts or ternary salt co-crystals, formulated as [HLf]·[Hip]·H2O (1), [HLf]·[BA]·[HBA]·H2O (2) and [HLf]·[BA]·[H2ip]·CH3OH·H2O (3). These pharmaceutical agents present uniform charge-assisted hydrogen-bonding networks between HLf cations and acidic coformers with the lattice capturing water molecules. Structural comparison of (2) and (3) indicated that a delicate balance of geometries and hydrogen-bonding partners is required for stacking to favor the formation of ternary salt co-crystals. Cocrystallization was able to overcome the water insolubility of lomefloxacin. Both the salt co-crystals display enhanced solubility and better pharmaceutical applicability. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel ferrocene derivatives containing pyrazolyl-moiety (4a–k, 5a–k) were synthesized. Their structures were characterized by 1H NMR, mass spectroscopy and element analysis. The crystals of isomeric compounds 4 and 5 were suitable for X-ray structural analysis. All the compounds were evaluated for their inhibitory activities against A549, HepG2 and MDA-MB-45 cell lines using the MTT method. Among them, compounds 4d, 4j and 4k exhibited comparable antitumor activities in vitro against A549 and MDA-MB-45 to the positive control 5-fluorouracil (5-FU). [Copyright &y& Elsevier]

The crystallization of norfloxacin, an antibacterial fluoroquinolone compound, with different benzenedicarboxylic acids yields five novel pharmaceutical salts via molecular recognition. X-ray single-crystal diffraction analyses reveal that these pharmaceutical agents present uniform charge-assistant hydrogen-bonding networks, which are in 1 : 1 stoichiometry of norfloxacin and dicarboxylate therein (with the exception of that with terephthalate). Unsubstituted benzenedicarboxylates (phthalate in 1, isophthalate in 2, and terephthalate in 3, respectively) are likely to crystallize with norfloxacin without lattice solvents, while the substituted isophthalate moieties (2-aminoisophthalate in 4 and 5-aminoisophthalate in 5) tend to form supramolecular adducts with the inclusion of water. Aromatic stacking interactions are present in all these structures, occurring between the fluoroquinolone and carboxylate phenyl rings (in 1–4) as well as between the fluoroquinolone planes (in 5). Thermal stability and solubility of all crystalline binary adducts have been determined. The effect of carboxylate counterions, substituents, and hydration states on the solubility and dissolution profile of drug salts 1–5 are investigated in pure water and 0.1 M HCl. After the formation of salts, the solubility increases at near neutral pH in almost all cases (except 3), but the order is changed in acidic medium. Phthalic acid shows evidence of a good candidate to enhance the solubility of fluoroquinolone drugs for the solubility of 1 is approximately 39 times as large as that of norfloxacin in pure water and also larger than that of norfloxacin in acidic system. For the isophthalates series, 2 has very poor solubility in 0.1 M HCl (only 0.06 times as that of Nf), while amino substituted isophthalates result in the enhancement of the solubility. Remarkably, crystal packing analyses of these pharmaceutical salts allow a possible correlation between the H-bonding prototypes and the solubility to be established. [ABSTRACT FROM AUTHOR]

Abstract: A series of N-((1,3-diphenyl-1H-pyrazol-4-yl)methyl)aniline derivatives (5a–8d) have been designed and synthesized, and their biological activities were also evaluated as potential antitumor and cyclin dependent kinase 2 (CDK2) inhibitors. Among all the compounds, compound 5a displayed the most potent CDK2/cyclin E inhibitory activity in vitro, with an IC50 of 0.98±0.06μM. Antitumor assays indicated that compound 5a owned high antiproliferative activity against MCF-7 and B16-F10 cancer cell lines with IC50 values of 1.88±0.11 and 2.12±0.15μM, respectively. Docking simulation was performed to insert compound 5a into the crystal structure of CDK2 at active site to determine the probable binding model. Based on the preliminary results, compound 5a with potent inhibitory activity in tumor growth may be a potential anticancer agent. [Copyright &y& Elsevier]

Abstract: The SAR study on a phage library-derived non-phosphorylated cyclic peptide ligand of Grb2-SH2 domain indicates that the configuration of the cyclization linkage is crucial for assuming the active binding conformation. When the thioether linkage was oxidized to the two chiral sulfoxides, the R-configured sulfoxide-cyclized peptide displayed 10–30 times more potency than the corresponding S-configured one in binding affinity to the Grb2-SH2 domain. In this paper, the solution structures of such a pair of sulfoxide-bridged cyclic peptide diastereoisomers, i.e., cyclo[CH2CO-Gla1-L-Y-E-N-V-G-NPG-Y-(R/S)C(O)10]-amide, were determined by NMR and molecular dynamics simulation. Results indicate that the consensus sequence of Y3-E4-N5-V6 in both diastereoisomers adopt a β-turn conformation; however, the R-configured peptide forms an extended structure with a circular backbone conformation, while the S-configured isomer forms a compact structure with key residues buried inside the molecule. The average root-mean-square deviations were found to be 0.756 and 0.804Å, respectively. It is apparent that the chiral S→O group played a key role in the solution structures of the sulfoxide-bridged cyclic peptides. The R-sulfoxide group forms an intramolecular hydrogen bond with the C-terminal amide, conferring a more rigid conformation with all residues protruding outside except for Leu2, in which the Gla1 and Tyr3 share an overlapping function as previous SAR studies proposed. Additionally, the extended structure endows a more hydrophilic binding surface of the R-configured peptide to facilitate its capture by its targeted protein. In comparison, the S-configured sulfoxide was embedded inside the ligand peptide leading to a compact structure, in which the essential residues of Gla1, Tyr3, and Asn5 form multiple intramolecular hydrogen bonds resulting in an unfavorable conformational change and a substantial loss of the interaction with the protein. The solution structures disclosed by our NMR and molecular dynamics simulation studies provide a molecular basis for understanding how the chirality of the cyclization linkage remarkably discriminates in terms of the binding affinity, thus advancing the rational design of potent non-phosphorylated inhibitors of Grb2-SH2 domain as antitumor agents. [Copyright &y& Elsevier]

This study evaluated the neurodevelopmental toxicity of isoniazid (INH) in zebrafish embryos and the underlying mechanism. Zebrafish embryos were exposed to different concentrations (2 mM, 4 mM, 8 mM, 16 mM, 32 mM) INH for 120 hpf. During the exposure period, the percentage of embryo/larva mortality, hatching, and morphological malformation were checked every 24 h until 120 hpf. The development of blood vessels in the brain was observed at 72 hpf and 120 hpf, and behavioral capacity and acridine orange (AO) staining were measured at 120 hpf. Alterations in the mRNA expression of apoptosis and dopamine signaling pathway related genes were assessed by real-time quantitative PCR (qPCR). INH considerably inhibited zebrafish embryo hatching and caused zebrafish larval malformation (such as brain malformation, delayed yolk sac absorption, spinal curvature, pericardial edema, and swim bladder defects). High concentration of INH (16 mM, 32 mM) even induced death of zebrafish. In addition, INH exposure markedly restrained the ability of the zebrafish autonomous movement, shortened the length of dopamine neurons and inhibited vascular development in the brain. No obvious apoptotic cells were observed in the control group, whereas considerable numbers of apoptotic cells appeared in the head of INH-treated larvae at 120 hpf. PCR results indicated that INH significantly raised the transcription levels of caspase-3 , -8 , -9 , and bax and significantly decreased bcl-2 and bcl-2/bax in the zebrafish apoptotic signaling pathway. INH also markedly decreased the genes related to dopamine signaling pathway (th1 , dat , drd1 , drd2a , drd3 , and drd4b). Experimental results indicated that INH had obvious neurodevelopmental toxicity in zebrafish. Persistent exposure to INH for 120 h caused apoptosis, decreased dopaminergic gene expression, altered vasculature, and reduced behaviors. Image 1 • INH impaired the development of vasculature and reduced the behavior of zebrafish. • INH induced brain apoptosis and increased the expression of apoptosis related genes. • INH inhibited dopamine neuron development and the expression of dopamine related genes. [ABSTRACT FROM AUTHOR]

• A novel series of rutaecarpine-based pde5 inhibitors were synthesized. • Compound 8i exhibited PDE5 inhibition with IC 50 values about 0.087 μM. • Compound 8i showed significant effects against scopolamine-induced cognitive impairment in vivo. A series of novel rutaecarpine derivatives were synthesized and subjected to pharmacological evaluation as PDE5 inhibitors. The structure–activity relationships were discussed and their binding conformation and simultaneous interaction mode were further clarified by the molecular docking studies. Among the 25 analogues, compound 8i exhibited most potent PDE5 inhibition with IC 50 values about 0.086 μM. Moreover, it also produced good effects against scopolamine-induced cognitive impairment in vivo. These results might bring significant instruction for further development of potential PDE5 inhibitors derived from rutaecarpine as a good candidate drug for the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]