Search

An inrush current is a transient current that results from a sudden change in the exciting voltage across a transformer's windings. Reducing the inrush current of transformers is desirable due to mechanical stresses and negligent operation of protective relay systems such as differential relays. This paper investigates the application of a saturated-core transformer as an inrush current limiter (ICL). Analytical methods of inrush current and its electromagnetic forces on transformer windings with and without application of proposed ICL are presented. Also, the core saturation of the ICL and transformer, in addition to the voltage drop on the ICL in transient and steady states, are investigated. A single-phase transformer is modeled in two dimensions (2-D), and the forces due to inrush current are calculated by the finite element method (FEM) in Maxwell software. The radial and axial force distributions of transformer windings with and without the ICL are investigated. The results show the capability of ICL to limit the transformer inrush current and reduction of its electromagnetic forces. Our simulations demonstrate a significant reduction in inrush current (75 %) using the proposed Inrush Current Limiter (ICL). Additionally, the ICL effectively mitigates electromagnetic forces within the transformer. Compared to a scenario without ICL, the ICL reduces radial forces by 80 % and axial forces by a substantial 90 %. These findings suggest that the ICL offers a promising solution for mitigating both inrush current and the associated electromagnetic forces in power transformers.

This paper presents an optimal framework for demand response aggregators in wholesale electricity markets. Demand response aggregators provide customers with flexible contracts in the proposed model. These contracts allow for hourly load reductions through load curtailment, load shifting, onsite generation utilization, and energy storage systems. The study suggests the price-based self-scheduling model for demand response aggregators, which seeks to maximize the aggregator's payoff for participation in day-ahead energy markets. The proposed model is implemented on a sample demand response aggregator with uncertainty and without uncertainty. Three methods, box, polyhedral, and ellipsoidal, based on robust optimization, are proposed for uncertainty modeling in this work, and their effectiveness is compared with each other. The results show that if the uncertainty is modeled using the polyhedral method, the value of the objective function will deviate by only 22.72 % compared to the case without uncertainty. However, this deviation in box and ellipsoidal methods is 118.48 % and 49.20 %, respectively, which shows the superiority of the polyhedral method compared to the oval and box methods.

The study was carried at the Zoology laboratory of Jijamata College, Bhende Tal-Newasa Dist-Ahmednagar, Maharashtra during April and May 2018 to find the most effective concentration of Azadirachta indica (V) plants extracts to control rice weevil in storage condition. The number of dead insects were increased with the increase of rate of the treatment. The insecticidal property of the plants also affects the adult emergence of rice weevil. Results showed that at all rates (2gm, 4gm and 6gm) of the treatments highest number of weevil was recorded in untreated control. From above finding it can be said that maximum of 84.15% rice weevil mortality at 28 days after treatment neem seed powder (6 gm) and minimum of 21.63% rice weevil mortality at 7 days after treatment neem bark powder (2 gm). So it can be said that though Azadirachta indica (V) plants extracts possess some insecticidal property, neem seed and leaf powder was found the best one to control rice weevil in storage condition. [ABSTRACT FROM AUTHOR]

The transportation sector is one of the main contributors to the emission of greenhouse gases globally, and the electrification of this sector can significantly reduce the emission of pollutants. The widespread connection of electric vehicles (EVs) to the power grid may bring challenges, such as increasing the peak load of the network. Therefore, the optimal use of EVs is necessary to improve the network’s economic, security, and stability indicators. This review article examines the deterministic control model and centralized control model, the types of EV models, and their tabular comparison. Additionally, expressing the communication standards to deal with compatibility challenges in charging stations, the effects of EV integration with the power grid, and various methods such as smart charging, dumb charging, and flexible charging are the main goals of this review article. In addition, since batteries play a crucial role in the electric vehicle industry, this research investigates the oldest type of rechargeable battery to the latest battery technology and the energy management system of these batteries. Finally, the authors have conducted studies on government incentives, the adverse effects of these incentives, and the combination of EVs with renewable energy sources.

Due to the rapid expansion of electric vehicles (EVs), they are expected to be one of the main contributors to transportation. The increasing use of fossil fuels as one of the most available energy sources has led to the emission of greenhouse gases, which will play a vital role in achieving a sustainable transportation system. Developed and developing countries have long-term plans and policies to use EVs instead of internal combustion vehicles and to use renewable energy to generate electricity, which increases the number of charging stations. Recently, to meet the charging demand for EVs, the main focus of researchers has been on smart charging solutions. In addition, maintaining power quality and peak demand for grids has become very difficult due to the widespread deployment of EVs as personal and commercial vehicles. This paper provides information on EV charging control that can be used to improve the design and implementation of charging station infrastructure. An in-depth analysis of EV types, global charging standards, and the architectures of AC-DC and DC-DC converters are covered in this review article. In addition, investigating the role of EV collectors, as well as EV penetration, in electric energy systems to facilitate the integration of electric energy systems with renewable energy sources is one of the main goals of this paper.

The optimal performance of a multi-chiller system (MCS) is the crucial factor in managing the expected power consumption (EPC). Also, the uncertainty of cooling demand in the industrial or residential sector plays a crucial role, which should be modeled and managed. So, the stochastic risk-constrained performance of the optimal chiller loading is studied in an uncertain environment in this paper. Scenario-based stochastic programming is applied to the provided case study to model the cooling demand uncertainty (CDU), and the downside risk constraints (DRC) are implemented to model the associated risks. The risk-averse performance of the MCS is compared with the risk-neutral one to show the positive effects of the DRC. The proposed model is implemented under the DICOPT solver in GAMS software. The comparison results show that the expected power consumption of MCS is increased slowly, while the expected risk-in-power consumption (ERIPC) is decreased promptly.

Combined Cooling, Heating, and Electrical (CCHP)-based microgrids meet various energy demands at the same time. Risk analysis of such CCHP-based microgrids under environmental and economic constraints is a challenging issue. Furthermore, high penetration of various renewable energy sources in such CCHP-based microgrids clouds the issue. Thus, Downside risk constraints technique (DRCT) is employed in this paper to manage and minimize the risk associated with various uncertainties in the studied sample CCHP-based microgrid under environmental and economic constraints. The uncertainties of solar radiation, wind speed, market tariff and cooling, heating, and electrical demands are considered, and the stochastic optimization approach is used to model the mentioned uncertainties. The effect of the Real-Time Pricing rate of the Demand Response Program (RTP-DRP) has been studied in this paper. By analyzing the obtained results, it can be found that with considering DRCT, the risk-in-cost (RC) level can plunge to 0 respectively by paying 2.61% and 1.68% without and with RTP-DRP.

In this paper, to get optimal scheduling of microgrids (MGs) in short-term, info-gap decision-theory (IGDT) is applied to assess load uncertainty. In order to provide a comprehensive load uncertainty study, best and worst possible conditions are evaluated using IGDT's functions of opportunity and robustness, respectively, in which risk-taker and risk-averse strategies are obtained while deterministic case study is also carried-out under the risk-neutral strategy. Real-time pricing (RTP) and time-of-use pricing (TOU) of demand response program (DRP) are applied to peak-load management. For each strategy, three cases as without DRP, TOU-DRP, and RTP-DRP are investigated. According to the results in the risk-neutral strategy, by applying TOU-DRP and RTP-DRP, operating cost is reduced about 2.5% and 6.6%, respectively. In the risk-averse strategy, by considering MG operating cost equal to $6,000, the MG will robust against load uncertainty up to 18.37%, 21.52%, and 24.82% for without DRP, TOU-DRP, and RTP-DRP cases, respectively. In the risk-taker strategy, MG operating cost for 28% of load reduction, operating costs will be equal to $3,698.12, $3,605.21, and $3,338.87 for without DRP, TOU-DRP, and RTP-DRP, respectively, in comparison with the risk-neutral strategy.

Risk analysis and scheduling of a Generation Company (GenCo) under uncertain environments are challenging issues. So, stochastic optimization and downside risk constraints approaches are used in this paper to model and manage the risk associated with various uncertainties. The presented GenCo model comprised five thermal units, photovoltaic systems, and wind farms. It is assumed that all thermal units, photovoltaic systems, and wind farms can participate in the energy market. In contrast, only thermal units can participate in the reserve market. The uncertainty of electricity and reserve market prices and output power of photovoltaic systems and wind farms are modeled via a stochastic optimization approach. Afterward, the downside risk constraints method is used to manage the risks associated with various uncertainties. By analyzing the obtained results, it can be seen that the level of the average risk can plunge to 0 by gaining 4.68% less average profit. So, the GenCo can be immune against considered uncertainties with gaining a little bit less profit. Furthermore, the offering strategy is studied in two risk-neutral and risk-averse strategies. Finally, the CPLEX solver of GAMS software is used to optimize the studied linear-based model of GenCo.

Electricity retailer is the most critical player in the restructured electricity market. Retailer's electricity procurement problem is a big challenge for them. Electricity retailer can purchase their energy from various options such as pool market, forward contracts, and etc. A relatively new way with a lesser investigation is the demand response exchange market. In this paper, the risk-constrained stochastic power procurement problem of electricity retailers is formulated by modeling the uncertainty of pool-market price and consumers' electricity demand. The Downside risk constraints (DRC) risk-evaluation method is used to obtain risk-based power procurement scheduling of electricity retailers. By using the proposed method, conservative electricity retailer can experience a scenario-independent strategy over the stochastic optimization. In other words, the proposed risk strategy is such that impose more cost for electricity retailer while having an equal cost in all scenarios. Based on the obtained results, the operation cost of electricity retailers in all scenarios is closed to about $4827570, which is a relatively zero-risk strategy due to equality overall scenarios. Besides, results are compared in two cases to demonstrate the advantages of the proposed risk-evaluation method. Also, the Pareto front between risk-in-cost and expected cost can introduce an optimal risk-strategy for electricity retailers in the presence of uncertainties. Finally, the risk-averse strategy of electricity retailer is proposed to obtain the retailer's optimal conservative schedule during power procurement in the presence of uncertainties.

The peer-to-peer (P2P) strategy as a new trading scheme has recently gained attention in local electricity markets. This is a practical framework to enhance the flexibility and reliability of energy hubs, specifically for industrial prosumers dealing with high energy costs. In this paper, a Norwegian industrial site with multi-energy hubs (MEHs) is considered, in which they are equipped with various energy sources, namely wind turbines (WT), photovoltaic (PV) systems, combined heat and power (CHP) units (convex and non-convex types), plug-in electric vehicles (EVs), and load-shifting flexibility. The objective is to evaluate the importance of P2P energy transaction with on-site flexibility resources for the industrial site. Regarding the substantial peak power charge in the case of grid power usage, this study analyzes the effects of P2P energy transaction under uncertain parameters. The uncertainties of electricity price, heat and power demands, and renewable generations (WT and PV) are challenges for industrial MEHs. Thus, a stochastically based optimization approach called downside risk constraint (DRC) is applied for risk assessment under the risk-averse and risk-neutral modes. According to the results, applying the DRC approach increased by 35% the operation cost (risk-averse mode) to achieve a zero-based risk level. However, the conservative behavior of the decision maker secures the system from financial losses despite a growth in the operation cost.

The concentrations of heavy metals (Cd, Cr, Ni and Zn) in sample water and organs (muscle, gills and liver) of fish Labeo rohita of river Godavari were analyzed. The heavy metal concentrations in sample water was in the order Cr.>Cd>Zn>Ni Accumulation of heavy metals in the organs of fish Labeo rohita was found in the order gills>muscle>liver. In the gills, cadmium was found maximum (2.89 μg/g dry weight), whereas chromium was minimum (0.63 μg/g dry weight). In the muscles, the value of cadmium was found maximium (2.29 μg/g dry weight) and chromium was minimium (0.65 μg/g). In the liver, cadmium and nickel were more concentrated compared to zinc and chromium. The concentration of heavy metals accumulated in gills and liver was found in the order Cd>Ni>Zn>Cr and in the muscles, it was found in the order Cd>Ni>Cr>Zn. As the fish Labeo rohita is largely consumed by people, it is essential to make awareness about water pollution and effects of heavy metals on human. The results suggest that the Godavari river system is contaminated with heavy metals. [ABSTRACT FROM AUTHOR]

Abstract This paper proposes a multi-objective benefit function for operation of active distribution systems considering demand response program (DRP) and energy storage system (ESS). In the active distribution system, active network management (ANM) is applied so that the distribution system equipment is controlled in real-time status based on the real-time measurements of system parameters (voltages and currents). The multi-objective optimization problem is solved using ε-constraint method, and a fuzzy satisfying approach has been employed to select the best compromise solution. Two different objective functions are considered as follows: benefit maximization of distribution company (DisCo); benefit maximization of distributed generation owner (DGO). To increase the benefits and efficient implementation of distributed generation (DG), DGO has installed battery as energy storage system (ESS) in parallel with DG unit. Consequently, DGO decides for the battery charging/discharging. DisCo has the ability to exchange energy with the upstream network and DGO. Also, DisCo focuses to study the effect of demand response program (DRP) on total benefit function and consequently its influence on the load profile has been discussed. This model is successfully applied to a 33-bus radial distribution network.

This study aimed to examine protective factors associated with resilience among unaccompanied refugee minors in comparison to their Norwegian peers and to examine associations between resilience factors and characteristics related to positive outcomes among unaccompanied minors. Data stem from the Pathways to Independence study conducted in Bergen municipality, Norway in 2018-2019 where 81 unaccompanied minors aged 15-20 participated (83.3% male; 80% response rate). An age- and sex-matched control group of 324 adolescents was retrieved from the youth@hordaland study conducted in Norway in 2012. Resilience factors were assessed by the Resilience Scale for Adolescents. Unaccompanied minors reported lower scores on Goal Orientation (d = 0.4), Social Competence (d = 0.4), and Social Support (d = 0.7) compared to Norwegian adolescents. Being male was associated with lower scores on Goal Orientation (standardized mean difference [SMD] = - 0.9) and Social Support (SMD = - 0.9) among unaccompanied minors, while being in frequent contact with family in the home country was associated with higher scores on all resilience factors (SMD range = 0.6-1.1). The number of leisure activities was associated with Social Competence (SMD = 0.22). There were no significant associations between the resilience factors and amount of support in the living arrangements or contact with the child welfare services. Unaccompanied minors reported fewer resilience factors compared to Norwegian adolescents, indicating that they may have different needs compared to other adolescents. Our study also suggests that frequent contact with family in the home country may be important to bolster positive development for unaccompanied minors after settlement., (© 2024. The Author(s).)

In both premenopausal and postmenopausal women, oestrogens play a critical role in the development of breast cancer. Aromatase is an enzyme that catalyses the final step in the biosynthesis of estrogen and has emerged as a promising target for therapeutic intervention. This study aimed to design and evaluate novel 1-(4-(benzamido)phenyl)-3-arylurea derivatives as potential aromatase inhibitors. Through molecular docking, promising leads were identified and synthesized. Spectroscopic techniques confirmed their structural integrity. Cytotoxicity against various cancer cell lines was assessed using MTT assay. Docking investigations against the aromatase enzyme (3s7s) elucidated binding interactions and energies. Compound 6g, exhibiting a binding energy of -8.6 kcal mol -1 and interacting with ALA306 and THR310 residues, showed the most promising activity. It demonstrated GI 50 values ranging from 14.46 μM, 13.97 μM, 11.35 μM, 11.58 μM, and 15.77 μM against A-498, NCI-H23, MDAMB-231, MCF-7, and A-549 respectively. Lastly, the physicochemical, and ADMET properties of the compound were predicted. These findings highlight the potential of 1-(4-(benzamido)phenyl)-3-arylureas as a new class of antitumor agents targeting aromatase. Their versatility and superior activity compared to standard chemotherapeutic agents, like doxorubicin, warrant further investigation for the development of broader-spectrum anticancer drugs., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Aims: The aim of the 'Pathways to Independence' study was to gain knowledge of how to facilitate a healthy development for unaccompanied refugee minors (URMs) after settling in Norwegian municipalities., Methods: The project is located in the URM child welfare services (URM CWS) of the Bergen municipality. We invited 101 URMs older than 15 years connected to the URM CWS to participate in a comprehensive survey. Of the invited, 81 consented to participate. The survey included questions on the user's experiences and satisfaction with the URM CWS, and questions related to schooling, social support and activities after settlement. We also included standardized and validated questionnaires on potential traumatic events, mental and somatic health, protective factors and quality of life. These questionnaires have previously been used in two Norwegian epidemiological studies, the 'Youth@Hordaland' and 'Young in Foster care', facilitating comparison of the results with other youth populations in Norway., Conclusion: Results from the project will be valuable in the process of reaching knowledge-based recommendations for successful settlement of URMs.

Aims: To describe the mental health of unaccompanied refugee minors (URMs) settled in Norway and compare their responses to an age- and sex-matched sample of Norwegian young people. Methods: The data were from the Pathways to Independence study of URMs aged 15-20 years ( n = 81; 82.7% male; response rate 80%) conducted in 2018-2019 in the Bergen municipality, Norway. The data from the URMs were linked to an age- and sex-matched group of young people from the Norwegian youth@hordaland study conducted in 2012 ( n = 324). Mental health was assessed by the Strengths and Difficulties Questionnaire (SDQ). Results: URMs were more likely to agree with most items pertaining to emotional problems, peer problems and prosocial subscales than Norwegian young people. Few differences were found for items on the conduct problems and hyperactivity-inattention problems scales. Poor psychometric properties, including weak factor loadings and low internal consistency, were detected for the SDQ subscales among URMs, except for the emotional problems subscale, indicating that the originally proposed five-factor model fitted the data poorly. Conclusions: URMs appear to have moderately more emotional problems than Norwegian young people. They are more likely to report being alone, getting along better with adults than with their peers and being bullied, but also report being more helpful and sharing with others. Studies with larger samples of URMs should determine the most appropriate factor structure of the SDQ when administered to URM samples.

Building knowledge on how child welfare services (CWS) should tailor services for unaccompanied refugee minors (URMs) is important. URMs and youth in foster care are high-risk groups taken care of by the CWS in Norway. Little is known on whether knowledge gained from youth in foster care can inform services for URMs, and if these groups are comparable in terms of experiences of potential traumatic events (PTEs) and post-traumatic stress disorder (PTSD) symptom load. Eighty-one URMs reported PTEs and PTSD-symptoms using an adapted version of the Child and Adolescent Trauma Screen (CATS). Responses were described and compared with a sample of 303 youth in foster care in linear regression models. We present relative risks (RR) and standardized mean differences (SMD) for the PTEs and the PTSD subscale and total score between the groups in forest plots. URMs had experienced a mean (standard deviation) of 6.4 (3.4) PTEs and 43.9% reported to have PTSD-symptoms at or above the clinical cut off. Compared to the foster youth, URMs reported more exposures of interpersonal violence outside of the family (RRs ranging from 66.4 [95%CI 18.1; 243.5) to 1.3 (1.0, 1.5)], and more PTSD-symptoms in the re-experiencing subscale [SMD = 0.3 (95% CI 0.1, 0.6)]. The frequency and types of PTEs and the PTSD-symptom load and profile among URMs and youth in foster care differed. Findings underscore the importance of qualified and targeted care for URMs, and that this care should differ to that of other high-risk groups in the CWS., (© 2021. The Author(s).)

Herein we report an efficient one-pot synthesis of [1,2,4]triazolo[1,5 a ][1,3,5]triazines from commercially available substituted aryl/heteroaryl aldehydes and substituted 2-hydrazinyl-1,3,5-triazines via N -bromosuccinimide (NBS) mediated oxidative C-N bond formation. Isomerisation of [1,2,4]triazolo[4,3- a ][1,3,5]triazines to [1,2,4]triazolo[1,5- a ][1,3,5]triazines is driven by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) affording both isomers with good to excellent yields (70-96%)., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Novel and effective anti-hypertensive agents are required to manage hypertension; therefore, we synthesised a novel antihypertensive drug from captopril and quercetin (cap-que) and explored its antihypertensive potential in a niosomal formulation via molecular hybridisation. The cap-que hybrid was synthesised, and its structure was characterised via NMR, FTIR, and HRMS. Niosomes were then loaded with cap-que using the thin-film hydration method. The particle size, polydispersity index, surface charge and drug entrapment efficiency (EE%) of the formulation were 418.8 ± 4.21 nm, 0.393 ± 0.063, 16.25 ± 0.21 mV, and 87.74 ± 2.82%, respectively. The drug release profile showed a sustained release of the active compound (43 ± 0.09%) from the niosomal formulation, compared to the parent drug (80.7 ± 4.68%), over 24 h. The cell viability study confirmed the biosafety of the formulation. The in vivo study in a rat model showed enhanced antihypertensive activity of the hybrid molecule and niosomal formulation which reduced systolic and diastolic pressure when compared to the individual, bare drugs. The findings of this study concluded that the antihypertensive potential of captopril can be enhanced by its hybridisation with quercetin, followed by niosomal nano drug delivery., (Copyright © 2021 Elsevier B.V. All rights reserved.)

There is a clear need to develop photostable chromophores for bioimaging with respect to the classically utilized green fluorescent dye fluorescein. Along these lines, we utilized a phosphorescent carboxy-substituted ruthenium(ii) polypyridyl [Ru(bipy)2(mcb)]2+ (bipy = 2,2'-bipyridyl and mcb = 4-carboxy-4'-methyl-2,2'-bipyridyl) complex. We developed two luminescent peptide conjugates of the cell-penetrating peptide Tat48-60 consisting of either [Ru(bipy)2(mcb)]2+ or 5(6)-carboxyfluorescein (5(6)-FAM) tethered on the Lys50 of the peptide through amide bond. We confirmed the efficient cellular uptake of both bioconjugates in HeLa cells by confocal microscopy and flow cytometry and proved that the ruthenium-based chromophore possesses enhanced photostability compared to a 5(6)-FAM-based peptide, after continuous laser scanning. Furthermore, we designed and developed a luminescent agent with high photostability, based on the ruthenium core, that could be selectively localized in cancer cells overexpressing the GnRH receptor (GnRH-R). To achieve this, we took advantage of the tumor-homing character of d-Lys6-GnRH which selectively recognizes the GnRH-R. The [Ru(bipy)2(mcb)]2+-d-Lys6-GnRH peptide conjugate was synthesized, and its cellular uptake was evaluated through flow cytometric analysis and live-cell imaging in HeLa and T24 bladder cancer cells as negative and positive controls of GnRH-R, respectively. Besides the selective targeting that the specific conjugate could offer, we also recorded high internalization levels in T24 bladder cancer cells. The ruthenium(ii) polypyridyl peptide-based conjugates we developed is an intriguing approach that offers targeted cell imaging in the Near Infrared region, and simultaneously paves the way for further advancements in the dynamic studies on cellular imaging.

Peptide-drug conjugates (PDCs) are gaining considerable attention as anti-neoplastic agents. However, their development is often laborious and time-consuming. Herein, we have developed and preclinically evaluated three PDCs with gemcitabine as the anticancer cytotoxic unit and D-Lys 6 -GnRH (gonadotropin-releasing hormone; GnRH) as the cancer-targeting unit. These units were tethered via acid-labile programmable linkers to guide a differential drug release rate from the PDC through a combination of ester or amide and "click" type oxime ligations. The pro-drugs were designed to enable the selective targeting of malignant tumor cells with linker guided differential drug release rates. We exploited the oxime bond responsiveness against the acidic pH of the tumor microenvironment and the GnRH endocytosis via the GnRH-R GPCR which is overexpressed on cancer cells. The challenging metabolic properties of gemcitabine were addressed during design of the PDCs. We developed a rapid (1 hour) and cost-effective "click" oxime bond ligation platform to assemble in one-pot the 3 desired PDCs that does not require purification, surpassing traditional time-ineffective and low yield methods. The internalization of the tumor-homing peptide unit in cancer cells, overexpressing the GnRH-R, was first validated through confocal laser microscopy and flow cytometry analysis. Subsequently, the three PDCs were evaluated for their in vitro antiproliferative effect in prostate cancer cells. Their stability and the release of gemcitabine over time were monitored in vitro in cell culture and in human plasma using LC-MS/MS. We then assessed the ability of the developed PDCs to internalize in prostate cancer cells and to release gemcitabine. The most potent analog, designated GOXG 1 , was used for pharmacokinetic studies in mice. The metabolism of GOXG 1 was examined in liver microsomes, as well as in buffers mimicking the pH of intracellular organelles, resulting in the identification of two metabolites. The major metabolite at low pH emanated from the cleavage of the pH-labile oxime bond, validating our design approach. NMR spectroscopy and in vitro radioligand binding assays were exploited for GOXG 1 to validate that upon conjugating the drug to the peptide, the peptide microenvironment responsible for its GnRH-R binding is not perturbed and to confirm its high binding potency to the GnRH-R. Finally, the binding of GOXG 1 to the GnRH-R and the associated elicitation of testosterone release in mice were also determined. The facile platform established herein for the rapid assembly of PDCs with linker controllable characteristics from aldehyde and aminooxy units through rapid "click" oxime ligation, that does not require purification steps, could pave the way for a new generation of potent cancer therapeutics, diagnostics and theranostics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor. Maximal surgical resection followed by radiotherapy and concomitant chemotherapy with temozolomide remains the first-line therapy, prolonging the survival of patients by an average of only 2.5 months. There is therefore an urgent need for novel therapeutic strategies to improve clinical outcomes. Reactive oxygen species (ROS) are an important contributor to GBM development. Here, we describe the rational design and synthesis of a stable hybrid molecule tethering two ROS regulating moieties, with the aim of constructing a chemopreventive and anticancer chemical entity that retains the properties of the parent compounds. We utilized the selective AT 1 R antagonist losartan, leading to the inhibition of ROS levels, and the antioxidant flavonoid quercetin. In GBM cells, we show that this hybrid retains the binding potential of losartan to the AT 1 R through competition-binding experiments and simultaneously exhibits ROS inhibition and antioxidant capacity similar to native quercetin. In addition, we demonstrate that the hybrid is able to alter the cell cycle distribution of GBM cells, leading to cell cycle arrest and to the induction of cytotoxic effects. Last, the hybrid significantly and selectively reduces cancer cell proliferation and angiogenesis in primary GBM cultures with respect to the isolated parent components or their simple combination, further emphasizing the potential utility of the current hybridization approach in GBM., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Peptide-drug conjugates have emerged as a potent approach to enhance the targeting and pharmacokinetic profiles of drugs. However, the impact of the linker unit has not been explored/exploited in depth. Gemcitabine (dFdC) is an anticancer agent used against a variety of solid tumours. Despite its potency, gemcitabine suffers mostly due to its unspecific toxicity, lack of targeting and rapid metabolic inactivation. To minimize these limitations and enable its targeting to tumours overexpressing the GnRH receptor, we examined the peptide-drug conjugation approach. Our design hypothesis was driven by the impact that the linker unit could have on the peptide-drug conjugate efficacy. Along these lines, in order to exploit the potential to manipulate the potency of gemcitabine through altering the linker unit we constructed three different novel peptide-drug conjugates assembled of gemcitabine, the tumour-homing peptide D-Lys 6 -GnRH and modified linker building blocks. Specifically, the linker was sculpted to either allow slow drug release (utilizing carbamate bond) or rapid disassociation (using amide and ester bonds). Notably, the new analogues possessed up to 95.5-fold enhanced binding affinity for the GnRH receptor (GnRH-R) compared to the natural peptide ligand D-Lys 6 -GnRH. Additionally, their in vitro cytotoxicity was evaluated in four different cancer cell lines. Their cellular uptake, release of gemcitabine and inactivation of gemcitabine to its inactive metabolite (dFdU) was explored in a representative cell line. In vitro stability and the consequent drug release were evaluated in cell culture medium and human plasma. In vivo pharmacokinetic studies were performed in mice, summarizing the relative stability of the three conjugates and the released levels of gemcitabine in comparison with dFdU. These studies suggest that the fine tuning of the linkage within a peptide-drug conjugate affects the drug release rate and its overall pharmaceutical profile. This could eventually emerge as an intriguing medicinal chemistry approach to optimize bio-profiles of prodrugs., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Clopidogrel bisulphate (CB) is a first line antiplatelet drug for treatment of myocardial infarction and stroke. Yet, its efficacy is limited by its poor solubility in intestinal pH, its main site of absorption. The main aim of this study is to enhance the intestinal release of CB by loading in cubosome nanoparticles. Glyceryl monooleate (GMO) based CB loaded cubosomes were prepared using a 3 3 factorial design to study the effect of polyvinyl alcohol (PVA), poloxamer 407 (PL407) concentrations and ratio of CB to the disperse phase on the average particle size, entrapment efficiency (%EE), in vitro release at 15 min (%Q 15 ), and their morphology using transmission electron microscopy (TEM). The release of the optimized formula was compared in buffer transition media (pH 1.2 for 2 h then pH 6.8 for 6 h) to free drug to study the effect of the changing pH in the gastrointestinal tract (GIT) on CB release. The antihaemostatic properties of the optimized formula were compared to the commercial product Plavix ® using bleeding time (BT) model in rabbits. The prepared cubosomes were in the nano range (115±6.47 to 248±4.63 nm) with high %EE (91.22±4.09% to 98.98±3.21%). The optimized formula showed significantly higher (p<0.05) CB release in intestinal pH and preserved the high% released (95.66±1.87%) in buffer transition release study compared to free drug (66.82±4.12%) as well as significantly (p<0.05) higher antihaemostatic properties with longer BT (628.47±6.12 s) compared to Plavix ® (412.43±7.97 s). Thus, cubosomes proved to be a successful platform to enhance the intestinal release of CB and improve its absorption.

Kinesin spindle protein (KSP) belongs to the kinesin superfamily of microtubule-based motor proteins. KSP is responsible for the establishment of the bipolar mitotic spindle which mediates cell division. Inhibition of KSP expedites the blockade of the normal cell cycle during mitosis through the generation of monoastral MT arrays that finally cause apoptotic cell death. As KSP is highly expressed in proliferating/cancer cells, it has gained considerable attention as a potential drug target for cancer chemotherapy. Therefore, this study envisaged to design novel KSP inhibitors by employing computational techniques/tools such as pharmacophore modelling, virtual database screening, molecular docking and molecular dynamics. Initially, the pharmacophore models were generated from the data-set of highly potent KSP inhibitors and the pharmacophore models were validated against in house test set ligands. The validated pharmacophore model was then taken for database screening (Maybridge and ChemBridge) to yield hits, which were further filtered for their drug-likeliness. The potential hits retrieved from virtual database screening were docked using CDOCKER to identify the ligand binding landscape. The top-ranked hits obtained from molecular docking were progressed to molecular dynamics (AMBER) simulations to deduce the ligand binding affinity. This study identified MB-41570 and CB-10358 as potential hits and evaluated these experimentally using in vitro KSP ATPase inhibition assays.

A novel series of 1,3,4-thiadiazole-thiazolone hybrids 5a-v were designed, synthesized, characterized, and evaluated against the basal and the microtubule (MT)-stimulated ATPase activity of Eg5. From the evaluated derivatives, 5h displayed the highest inhibition with an IC 50 value of 13.2 µM against the MT-stimulated Eg5 ATPase activity. Similarly, compounds 5f and 5i also presented encouraging inhibition with IC 50 of 17.2 µM and 20.2 µM, respectively. A brief structure-activity relationship (SAR) analysis indicated that 2-chloro and 4-nitro substituents on the phenyl ring of the thiazolone motif contributed significantly to enzyme inhibition. An in silico molecular docking study using the crystal structure of Eg5 further supported the SAR and reasoned the importance of crucial molecular protein-ligand interactions in influencing the inhibition of the ATPase activity of Eg5. The magnitude of the electron-withdrawing functionalities over the hybrids and the critical molecular interactions contributed towards higher in vitro potency of the compounds. The drug-like properties of the synthesized compounds 5a-v were also calculated based on the Lipinski's rule of five and in silico computation of key pharmacokinetic parameters (ADME). Thus, the present work unveils these hybrid molecules as novel Eg5 inhibitors with promising drug-like properties for future development., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A novel series of 4,6-disubstituted pyrazolo[3,4-d]pyrimidines (7-43) bearing various anilines at C-4 position and thiophenethyl or thiopentane moieties at C-6 position have been designed and synthesized by molecular hybridization approach. All the synthesized compounds were evaluated for in vitro CDK2/cyclin E and Abl kinase inhibitory activity as well as anti-proliferative activity against K-562 (chronic myelogeneous leukemia), and MCF-7 (breast adenocarcinoma) cell lines. The structure-activity relationship (SAR) studies revealed that compounds with thiophenethyl group at C-6 with mono-substituted anilines at C-4 exhibited better CDK2 inhibitory activity compared to alkyl group (thiopentane) at C-6 and di-substituted anilines at C-4 of the scaffold. In particular, compounds having 2-chloro, 3-nitro and 4-methylthio aniline groups at C-4 displayed significant enzymatic inhibitory activity against CDK2 with single digit micromolar IC 50 values. The in silico molecular docking studies suggested possible binding orientation and the binding energies were in agreement with the observed SAR as well as experimental results. In addition, some of the synthesized compounds showed anti-proliferative effects against K-562 and MCF-7 cancer cell lines with IC 50 values in a micromolar range. Thus, the synthesized compounds could be considered as new anticancer hits for further lead optimization., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Quercetin is a flavonoid presenting cytotoxicity against different cancer cell lines. We hypothesized that its core could serve as a scaffold for generating more potent compounds. A quercetin-alanine bioconjugate was synthesized, its cellular internalization was monitored through confocal microscopy and its cytotoxic activity was explored against ten different cell lines. The bioconjugate consistently illustrated enhanced cytotoxic activity with respect to the parent compound. A threefold enhancement in its cytotoxicity was revealed for HeLa, A549, MCF-7 and LNCaP cells. In silico studies suggested that quercetin-alanine possesses enhanced binding affinity to human estrogen receptor alpha corroborating to its activity to MCF-7, overexpressing this receptor. Spectrofluorimetric, calorimetric and in silico studies revealed that quercetin-alanine binds primarily to Sudlow site I of serum albumin mainly through hydrogen bonding. Through this array of experiments we discovered that the specific compound bears a more refined pharmaceutical profile in contrast to quercetin in terms of cytotoxicity, while at the same time preserves its affinity to serum albumin. Natural products could thus offer a potent scaffold to develop bioconjugates with amplified therapeutic window.

Pyrazolo[4,3-d]pyrimidine, a fused heterocycle bearing pyrazole and pyrimidine portions has gained a significant attention in the field of bioorganic and medicinal chemistry. Pyrazolo[4,3-d]pyrimidine derivatives have demonstrated numerous pharmacological activities particularly, anti-cancer, anti-infectious, phosphodiesterase inhibitors, adenosine antagonists and cytokinin antagonists etc. This review extensively unveils the synthetic and pharmacological diversity with special emphasis on structural variations around pyrazolo[4,3-d]pyrimidine scaffold. This endeavour has thus uncovered the medicinal worthiness of pyrazolo[4,3-d]pyrimidine framework. To the best of our knowledge this review is the first compilation on synthetic, medicinal and structure activity relationship (SAR) aspects of pyrazolo[4,3-d]pyrimidines since 1956., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The present study focused to optimize dual coated multiparticulates using Box-Behnken Experimental Design and in-silico simulation using GastroPlusTM software. The optimized formulations (OB1 and OB2) were comparatively evaluated for particle size, morphological, in vitro drug release, and in vivo permeation studies. In silico simulation study predicted the in vivo performance of the optimized formulation based on in-vitro data. Results suggested that optimized formulation was obtained using maximum content of Eudragit FS30D and minimum drying time (2 min). In vitro data corroborated that curcumin release was completely protected from premature drug release in the proximal part of gastro intestinal tract and successfully released to the colon (95%) which was closely predicted (90.1 %) by GastroPlusTM simulation technique. Finally, confocal laser scanning microscopy confirmed the in-vitro findings wherein maximum intensity was observed with OB1 treated group suggesting successful delivery of OB1 to the colon for enhanced absorption as predicted in regional absorption profile in ascending colon (30.9%) and caecum (23.2%). Limited drug absorption was predicted in small intestine (1.5-8.7%). The successful outcomes of the research work minimized the release of curcumin in the upper gastric tract and the maximized drug access to the colon (pH 7.4) as prime concern., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Anti-apoptotic proteins, like the Bcl-2 family proteins, present an important therapeutic cancer drug target. Their activity is orchestrated through neutralization upon interaction of pro-apoptotic protein counterparts that leads to immortality of cancer cells. Therefore, generating compounds targeting these proteins is of immense therapeutic importance. Herein, Induced Fit Docking (IFD) and Molecular Dynamics (MD) simulations were performed to rationally design quercetin analogues that bind in the BH3 site of the Bcl-xL protein. IFD calculations determined their binding cavity while Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics Generalised Born Surface Area (MM-GBSA) calculations provided an insight into the binding enthalpies of the analogues. The quercetin analogues were synthesized and their binding to Bcl-xL was verified with fluorescence spectroscopy. The binding affinity and the thermodynamic parameters between Bcl-xL and quercetin-glutamic acid were estimated through Isothermal Titration Calorimetry. 2D 1 H- 15 N HSQC NMR chemical shift perturbation mapping was used to chart the binding site of the quercetin analogues in the Bcl-xL that overlapped with the predicted poses generated by both IFD and MD calculations. Furthermore, evaluation of the four conjugates against the prostate DU-145 and PC-3 cancer cell lines, revealed quercetin-glutamic acid and quercetin-alanine as the most potent conjugates bearing the higher cytostatic activity. This pinpoints that the chemical space of natural products can be tailored to exploit new hits for difficult tractable targets such as protein-protein interactions.

The potential to heighten the efficacy of antiangiogenic agents was explored in this study based on active targeting of tumor cells overexpressing the gonadotropin-releasing hormone receptor (GnRH-R). The rational design pursued focused on five analogues of a clinically established antiangiogenic compound (sunitinib), from which a lead candidate (SAN1) was conjugated to the targeting peptide [d-Lys(6)]-GnRH, generating SAN1GSC. Conjugation of SAN1 did not disrupt any of its antiangiogenic or cytotoxic properties in GnRH-R-expressing prostate and breast tumor cells. Daily SAN1GSC treatments in mouse xenograft models of castration-resistant prostate cancer resulted in significant tumor growth delay compared with equimolar SAN1 or sunitinib alone. This efficacy correlated with inhibited phosphorylation of AKT and S6, together with reduced Ki-67 and CD31 expression. The superior efficacy of the peptide-drug conjugate was also attributed to the finding that higher amounts of SAN1 were delivered to the tumor site (∼4-fold) following dosing of SAN1GSC compared with equimolar amounts of nonconjugated SAN1. Importantly, treatment with SAN1GSC was associated with minimal hematotoxicity and cardiotoxicity based on measurements of the left ventricular systolic function in treated mice. Our results offer preclinical proof-of-concept for SAN1GSC as a novel molecule that selectively reaches the tumor site and downregulates angiogenesis with negligible cardiotoxicity, thus encouraging its further clinical development and evaluation., (©2015 American Association for Cancer Research.)

Recent science evidenced the interlinkage of oxidative stress and cancer. Due to the inherent complexity of cancer and its accompanying effect of oxidative stress, novel molecules, containing combinatorial functionalities should be targeted. Herein, we synthesized gemcitabine-5'-O-lipoate derived from a regioselective coupling of the chemotherapeutic drug gemcitabine (GEM), a first-line agent for cancer therapy and α-lipoic acid (LA), a potent antioxidant. gemcitabine-5'-O-lipoate was obtained in 4 chemical steps. To avoid the tedious and laborious chemical steps we also utilized biocatalysis using immobilized Candida antarctica lipase B (CALB), and the optimum conditions for the regioselective and one-pot synthesis of gemcitabine-5'-O-lipoate were established by exploiting different solvents (organic solvents and ionic liquids) and enzyme immobilization (acrylic resin and carbon nanotubes). Cytotoxic activity of co-administrating GEM and LA was proven to be synergistic against non-small cell lung cancer cells whereas antagonistic for bladder cancer cells. In contrast, the gemcitabine-5'-O-lipoate hybrid was found to be superior to the parent compounds against both non-small cell lung cancer and bladder cancer cells as also was found to preserve the redox activity of the parent compound LA. The regioselective biotransformation mediated synthesis of the anticancer-antioxidant hybrid illustrates the capacity of biocatalysis to act as an asset in molecular hybridization techniques., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Gemcitabine, a drug with established efficacy against a number of solid tumors, has therapeutic limitations due to its rapid metabolic inactivation. The aim of this study was the development of an innovative strategy to produce a metabolically stable analogue of gemcitabine that could also be selectively delivered to prostate cancer (CaP) cells based on cell surface expression of the Gonadotropin Releasing Hormone-Receptor (GnRH-R). The synthesis and evaluation of conjugated molecules, consisting of gemcitabine linked to a GnRH agonist, is presented along with results in androgen-independent prostate cancer models. NMR and ligand binding assays were employed to verify conservation of microenvironments responsible for binding of novel GnRH-gemcitabine conjugates to the GnRH-R. In vitro cytotoxicity, cellular uptake, and metabolite formation of the conjugates were examined in CaP cell lines. Selected conjugates were efficacious in the in vitro assays with one of them, namely, GSG, displaying high antiproliferative activity in CaP cell lines along with significant metabolic and pharmacokinetic advantages in comparison to gemcitabine. Finally, treatment of GnRH-R positive xenografted mice with GSG showed a significant advantage in tumor growth inhibition when compared to gemcitabine.

Alkylation of sensitive amino acids during synthesis of biologically important peptides is a common and well-documented problem in Fmoc-based strategy. Herein, we probed for the first time an unexpected S-alkylation of Cys-containing peptides that occur during the final TFA cleavage of peptides from the Wang solid support. Through a battery of approaches (NMR, UV and LC-MS) the formed by-product was assigned as the alkylation of the cysteine sulfydryl group by the p-hydroxyl benzyl group derived from the acidic Wang linker decomposition. Factors affecting this side reaction were monitored and a protocol that minimizes the presence of the by-product is reported.

The goal of this study was to monitor the anti-proliferative activity of Rosmarinus officinalis and Salvia officinalis extracts against cancer cells and to correlate this activity with their phytochemical profiles using liquid chromatography/diode array detection/electrospray ion trap tandem mass spectrometry (LC/DAD/ESI-MS(n)). For the quantitative estimation of triterpenic acids in the crude extracts an NMR based methodology was used and compared with the HPLC measurements, both applied for the first time, for the case of betulinic acid. Both extracts exerted cytotoxic activity through dose-dependent impairment of viability and mitochondrial activity of rat insulinoma m5F (RINm5F) cells. Decrease of RINm5F viability was mediated by nitric oxide (NO)-induced apoptosis. Importantly, these extracts potentiated NO and TNF-α release from macrophages therefore enhancing their cytocidal action. The rosemary extract developed more pronounced antioxidant, cytotoxic and immunomodifying activities, probably due to the presence of betulinic acid and a higher concentration of carnosic acid in its phytochemical profile., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The localization of manganese superoxide dismutase (MnSOD) was determined using immunohistochemistry of various tissues of normal and transgenic mice which express the human enzyme, with emphasis on studies of mouse kidney and lung. Mouse kidney and lung were studied using both frozen section analysis and paraffin sections following fixation in a variety of fixatives. Formalin fixation resulted in a loss of antigenicity, while fixation in zinc formalin or B5 fixative gave results similar to those from frozen sections. Immunoperoxidase studies using antibodies to MnSOD showed greater staining in transgenic kidney or lung than in identical tissues in normal mice when appropriate fixation was used. In contrast, equal immunostaining was obtained in kidney or lung from normal and transgenic mice when antibodies to catalase or copper zinc superoxide dismutase were utilized. Immunogold ultrastructural analysis of MnSOD localization for lung and kidney was also performed. As compared to normal mice, transgenic mice exhibited greater staining of the mitochondria of kidney interstitial fibroblasts and glomerular, endothelial, and smooth muscle cells. In the lungs of transgenic animals, all cells showed increased staining; smooth muscle cells demonstrated the most marked increase in immunolabelling. The results indicate that these transgenic mice overexpress MnSOD in their mitochondria, and that this occurs selectively in at least some mesenchymal tissues.