Designing and Synthesis of Novel Celecoxib Derivatives with Aminosulfonylmethyl and Azidomethyl Substituents as Selective Cyclooxygenase-2 Inhibitors

Abstract: Introduction: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are used in treating pathologic conditions such as fever, pain and inflammation by inhibiting cyclooxygenase and consequently prostaglandin production. Recently , the discovery of different isoforms of this enzyme, Cyclooxygenase-1 (COX-1) and Cyclooxygense-2 (COX-2), has led to the synthesis and introduction of novel drugs with selective inhibitory effect on COX-2, the isoform produced in pathologic conditions (celecoxib in 1997 and rofecoxib in 1999). This study was carried out to design and synthesize two novel celecoxib derivatives with potential selective COX-2 inhibitory activity. Method: The derivatives were designed according to the Structure-Activity Relationship (SAR) data of selective COX-2 inhibitors. The condensation reaction of 4-hydrazinobenzoic acid and 4,4,4-triflouro-1-p-tolylbutane-1,3-dione led to the formation of 4-(5-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoic acid [8]. The carboxyl group of this acid was reduced to hydroxyl and then converted to chloride by freshly distilled thyonyl chloride. Successive reaction of chloride derivative with sodium sulfite, phosphrous pentachloride and ammonia led to the formation of sulfonamide derivative and reaction of it with sodium azide led to the azide analogue. Results: About 4 grams of each derivative has been synthesized (total yield 60-70%) and their chemical structures have been verified using appropriate spectroscopic methods. Conclusion: In this study, two novel celecoxib analogues with a methylene bridge distance between sulfonamide and azide functional groups and the rest of the molecule were designed and synthesized according to the SAR data of selective COX-2 inhibitors. This methylene group brings the pharmacophoric sulfonamide and azide functional groups closer to the binding site and leads to better binding. Furthermore, this methylene group provides free rotation to pharmacophore to attain appropriate conformation for better binding. Hopefully, pharmacological evaluation of derivatives, which is currently in progress, will confirm these assumptions. Keywords: Synthesis, Design, Nonsteroidal anti-inflammatory drugs (NSAIDs), Cyclooxygenase, Rofecoxib, Celecoxi

Golgi localized β1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLCε to regulate cardiac hypertrophy.

Increased adrenergic tone resulting from cardiovascular stress leads to development of heart failure, in part, through chronic stimulation of β1 adrenergic receptors (βARs) on cardiac myocytes. Blocking these receptors is part of the basis for β-blocker therapy for heart failure. Recent data demonstrate that G protein-coupled receptors (GPCRs), including βARs, are activated intracellularly, although the biological significance is unclear. Here we investigated the functional role of Golgi βARs in rat cardiac myocytes and found they activate Golgi localized, prohypertrophic, phosphoinositide hydrolysis, that is not accessed by cell surface βAR stimulation. This pathway is accessed by the physiological neurotransmitter norepinephrine (NE) via an Oct3 organic cation transporter. Blockade of Oct3 or specific blockade of Golgi resident β1ARs prevents NE dependent cardiac myocyte hypertrophy. This clearly defines a pathway activated by internal GPCRs in a biologically relevant cell type and has implications for development of more efficacious β-blocker therapies

Functional selectivity of GPCR-directed drug action through location bias.

G-protein-coupled receptors (GPCRs) are increasingly recognized to operate from intracellular membranes as well as the plasma membrane. The β 2 -adrenergic GPCR can activate G s -linked cyclic AMP (G s -cAMP) signaling from endosomes. We show here that the homologous human β 1 -adrenergic receptor initiates an internal G s -cAMP signal from the Golgi apparatus. By developing a chemical method to acutely squelch G-protein coupling at defined membrane locations, we demonstrate that Golgi activation contributes significantly to the overall cellular cAMP response. Golgi signaling utilizes a preexisting receptor pool rather than receptors delivered from the cell surface, requiring separate access of extracellular ligands. Epinephrine, a hydrophilic endogenous ligand, accesses the Golgi-localized receptor pool by facilitated transport requiring the organic cation transporter 3 (OCT3), whereas drugs can access the Golgi pool by passive diffusion according to hydrophobicity. We demonstrate marked differences, among both agonist and antagonist drugs, in Golgi-localized receptor access and show that β-blocker drugs currently used in the clinic differ markedly in ability to antagonize the Golgi signal. We propose \u27location bias\u27 as a new principle for achieving functional selectivity of GPCR-directed drug action

Analysis of Spatial Inequalities in Tehran Metropolis

Purpose: Nowadays, Spatial and social inequalities are universal and expanding phenomenon. Identification and spatial analysis of social, economic and ecological inequalities in metropolises is one of the essential and basic proceeding for planning and achieving urban sustainable development. Aims to reviews the quality of spatial differentiations between the 374 neighborhoods of Tehran metropolis. Methodology: The method of the research is descriptive-analytic. To identify regions’ development levels in Tehran, 10 sub-criteria in the form of 3 main criteria were used. With Using of AHP method and EXPERT CHOISE software each criteria and sub-criteria mutually were compared relative to each other, evaluated, and scored. Finally, by the method of hierarchical clustering, Tehran metropolis neighborhoods in terms of ranking of development at five levels of developed, relatively developed, medium developed, less developed, and underdeveloped regions, were clustered and in the Arc GIS settings were displayed as a map. Findings: The result of the indicators review shows that Tehran metropolis lacks socio-physical unity and spatial differentiations between the north and south of it remain still as the main feature of the spatial structure of Tehran metropolis. Originality/Value: The present study believes that the continuance of the current procedure, not only in Tehran but also at the national level is the main challenge over the way to achieve urban sustainable development and a good city

Investigation and identification of social harms in the new city of Sahand, Tabriz (With emphasis on Mehr housing)

Purpose: With the increase of Iran's urban population, large cities faced many problems and new cities were located and built to attract population overflow in the area of these cities. The new city of Sahand was built to reduce the demographic, economic, social and physical problems of the metropolis of Tabriz in the sphere of influence of this city. With the creation of Mehr housing in phases 2, 3 and 4 of this city, a new issue was raised. This article seeks to examine and identify the social issues and problems of this city, prioritize them and identify solutions to reduce the impact. Methodology: The research method used in this research is applied and survey. Findings: Results show that the most important problems are: drug use, class differences, cultural poverty, distrust of neighbors, distrust of city officials, economic poverty, presence Thugs, the presence of badly supervised women, unusual relationships between girls and boys, harassment of women, quarrels and conflicts, running away from home, begging, unconventional relationships between married men and women, child abuse and white marriage, relationships Poor neighborhood, general dissatisfaction with living conditions, feeling of insecurity in parks and gardens, inadequate lighting and lighting of roads, flooded roads, traffic jams and the problem of parking cars, unsuitable sidewalks, lack of medical centers, lack of playgrounds for children and adolescents, Lack of green space, inadequate garbage collection system, low quality of housing, lack of recreational space for citizens, etc., which are the most important factors in the occurrence and emergence of social harms in this city. Originality/Value: In this paper, investigation and identification of social harms in the new city of Sahand, Tabriz (With emphasis on Mehr housing) is done

Synthesis, in vitro antifungal evaluation and in silico study of 3-azolyl-4-chromanone phenylhydrazones

BACKGROUND: The currently available antifungal drugs suffer from toxicity, greatest potential drug interactions with other drugs, insufficient pharmacokinetics properties, and development of resistance. Thus, development of new antifungal agents with optimum pharmacokinetics and less toxicity is urgent task. In the search for new azole antifungals, we have been previously described azolylchromanone oxime ethers as rigid analogs of oxiconazole. In continuation of our work, we incorporated phenylhydrazone moiety instead of oxime ether fragment in azolylchromanone derivatives. METHODS: The 3-azolyl-4-chromanone phenylhydrazones were synthesized via ring closure of 2-azolyl-2'-hydroxyacetophenones and subsequent reaction with phenylhydrazine. The biological activity of title compounds was evaluated against different pathogenic fungi including Candida albicans, Saccharomyces cerevisiae, Aspergillus niger, and Microsporum gypseum. Docking study, in silico toxicity risks and drug-likeness predictions were used to better define of title compounds as antifungal agents. RESULTS: The in vitro antifungal activity of compounds based on MIC values revealed that all compounds showed good antifungal activity against C. albicans, S. cerevisiae and M. gypseum at concentrations less than 16 μg/mL. Among the test compounds, 2-methyl-3-imidazolyl derivative 3b showed the highest values of drug-likeness and drug-score. CONCLUSION: The 3-azolyl-4-chromanone phenylhydrazones considered as analogs of 3-azolyl-4-chromanone oxime ethers basically designed as antifungal agents. The antifungal activity of title compounds was comparable to that of standard drug fluconazole. The drug-likeness data of synthesized compounds make them promising leads for future development of antifungal agents

The α-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the β2-Adrenergic Receptor.

Arrestin domain-containing protein 3 (ARRDC3) is a member of the mammalian α-arrestin family, which is predicted to share similar tertiary structure with visual-/β-arrestins and also contains C-terminal PPXY motifs that mediate interaction with E3 ubiquitin ligases. Recently, ARRDC3 has been proposed to play a role in regulating the trafficking of G protein-coupled receptors, although mechanistic insight into this process is lacking. Here, we focused on characterizing the role of ARRDC3 in regulating the trafficking of the β2-adrenergic receptor (β2AR). We find that ARRDC3 primarily localizes to EEA1-positive early endosomes and directly interacts with the β2AR in a ligand-independent manner. Although ARRDC3 has no effect on β2AR endocytosis or degradation, it negatively regulates β2AR entry into SNX27-occupied endosomal tubules. This results in delayed recycling of the receptor and a concomitant increase in β2AR-dependent endosomal signaling. Thus, ARRDC3 functions as a switch to modulate the endosomal residence time and subsequent intracellular signaling of the β2AR

Identifying Defects Related to the Order in which Messages are Received in Message-Passing Systems

Improving the quality of software artifacts and products is an essential activity for everyone working on the development of software. Testing is one approach to reveal defects and faults in software. In recent years, message-passing systems have grown to a significant degree due to the rise of distributed systems, embedded systems, and so forth. In message-passing systems, components communicate with each other through sending and receiving messages. This message-passing mechanism introduces new opportunities for testing programs due to the fact that the time a message is delivered is not guaranteed, so the order in which messages are delivered is also not guaranteed. This non-determinism introduces interleaving and parallelization and subsequently a new source of software defects like race conditions. In this thesis, we have explained a new approach to testing a given component for identifying software faults related to the order in which messages are received by that component. We reorder messages coming to a certain component and deliver them in a different distinct ordering each time. We have three different methods for achieving message reordering: Blocking, Buffering, and Adaptive Buffering. We evaluate the effectiveness of our new testing methods using four metrics: Ordering Coverage, Coverage Rate, Slowdown Overhead, and Memory Overhead. We have implemented our Reordering Framework on QNX Neutrino 6.5.0 and compared our reordering methods with each other and with the naive random case using our experiments. We have also showed that our testing approach applies to real programs and can reveal real bugs in software

A crystallographic and theoretical study of an (E)-2-Hydroxyiminoethanone derivative: prediction of cyclooxygenase inhibition selectivity of stilbenoids by MM-PBSA and the role of atomic charge

We recently reported that a hydroxyiminoethanone derivative behaves as a highly selective COX-1 inhibitor (COX-1 SI= 833), and also an interesting scaffold with unique characteristics. In the current study, a comprehensive crystallographic and computational study was performed to elucidate its conformational stability and pharmacological activity. Its conformational energy was studied at the B3LYP/6-311G** level of theory and compared to the single-crystal X-ray data. In addition, computational studies of three structurally different stilbenoid derivatives used as selective COX-1 or COX-2 inhibitors were performed to predict their COX selectivity potentials. Flexible docking was performed for all compounds at the active site of both COX-1 and COX-2 enzymes by considering some of the key residues as flexible during the docking operation. In the next step, molecular dynamic simulation and binding free energy calculations were performed by MM-PBSA. Final results were found to be highly dependent on the atomic charges of the inhibitors and the choice of force field used to calculate the atomic charges. The binding conformation of the hydroxyiminoethanone derivative is highly correlated with the type of COX isoform inhibited. Our predictive approach can truly predict the cyclooxygenase inhibition selectivity of stilbenoid inhibitors

Designing Privacy-Enhanced Interfaces on Digital Tabletops for Public Settings

Protection of personal information has become a critical issue in the digital world. Many companies and service provider websites have adopted privacy policies and practices to protect users’ personal information to some extent. In addition, various governments are adopting privacy protection legislation. System developers, service providers, and interface designers play an important role in determining how to make systems fulfill legal requirements and satisfy users. The human factor requirements for effective privacy interface design can be categorized into four groups: (1) comprehension, (2) consciousness, (3) control, and (4) consent (Patrick & Kenny, 2003). Moreover, the type of technology that people are engaged with has a crucial role in determining what type of practices should be adopted. As Weiser (1996) envisioned, we are now in an “ubiquitous computing” (Ubicomp) era in which technologies such as digital tabletops (what Weiser called LiveBoards) are emerging for use in public settings. The collaborative and open nature of this type of smart device introduces new privacy threats that have not yet been thoroughly investigated and as a result have not been addressed in companies’ and governmental privacy statements and legislation. In this thesis, I provide an analytical description of the privacy threats unique to tabletop display environments. I then present several design suggestions for a tabletop display interface that addresses and mitigates these threats, followed by a qualitative evaluation of these designs based on Patrick and Kenny’s (2003) model. Results show that most participants have often experienced being shoulder-surfed or had privacy issues when sharing information with someone in a collaborative environment. Therefore, they found most of the techniques designed in this thesis helpful in providing information privacy for them when they are engaged with online social activities on digital tabletops in public settings. Among all of the proposed tested designs, the first three have proven to be effective in providing the required privacy. However, designs 4 and 5 had some shortfalls that made them less helpful for participants. The main problem with these two designs was that participants had difficulty understanding what they had to do in order to complete the given tasks