Sulfadiazine Exerts Potential Anticancer Effect in HepG2 and MCF7 Cells by Inhibiting TNFα, IL1b, COX-1, COX-2, 5-LOX Gene Expression: Evidence from In Vitro and Computational Studies.

Drug repurposing is a promising approach that has the potential to revolutionize the drug discovery and development process. By leveraging existing drugs, we can bring new treatments to patients more quickly and affordably. Anti-inflammatory drugs have been shown to target multiple pathways involved in cancer development and progression. This suggests that they may be more effective in treating cancer than drugs that target a single pathway. Cell viability was measured using the MTT assay. The expression of genes related to inflammation (TNFa, IL1b, COX-1, COX-2, and 5-LOX) was measured in HepG2, MCF7, and THLE-2 cells using qPCR. The levels of TNFα, IL1b, COX-1, COX-2, and 5-LOX were also measured in these cells using an ELISA kit. An enzyme binding assay revealed that sulfadiazine expressed weaker inhibitory activity against COX-2 (IC50 = 5.27 µM) in comparison with the COX-2 selective reference inhibitor celecoxib (COX-2 IC50 = 1.94 µM). However, a more balanced inhibitory effect was revealed for sulfadiazine against the COX/LOX pathway with greater affinity towards 5-LOX (IC50 = 19.1 µM) versus COX-1 (IC50 = 18.4 µM) as compared to celecoxib (5-LOX IC50 = 16.7 µM, and COX-1 IC50 = 5.9 µM). MTT assays revealed the IC50 values of 245.69 ± 4.1 µM and 215.68 ± 3.8 µM on HepG2 and MCF7 cell lines, respectively, compared to the standard drug cisplatin (66.92 ± 1.8 µM and 46.83 ± 1.3 µM, respectively). The anti-inflammatory effect of sulfadiazine was also depicted through its effect on the levels of inflammatory markers and inflammation-related genes (TNFα, IL1b, COX-1, COX-2, 5-LOX). Molecular simulation studies revealed key binding interactions that explain the difference in the activity profiles of sulfadiazine compared to celecoxib. The results suggest that sulfadiazine exhibited balanced inhibitory activity against the 5-LOX/COX-1 enzymes compared to the selective COX-2 inhibitor, celecoxib. These findings highlight the potential of sulfadiazine as a potential anticancer agent through balanced inhibitory activity against the COX/LOX pathway and reduction in the expression of inflammatory genes.

Circulating miR-199a and long noncoding-RNA ANRIL as Promising Diagnostic Biomarkers for Inflammatory Bowel Disease.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD), involving both Crohn's disease (CD) and ulcerative colitis (UC), represents a chronic, immune-mediated inflammatory disease due to an uncontrolled, ongoing inflammatory response to intestinal bacteria in those with genetic susceptibility. MicroRNA (miRNA) extrusion from relevant remote organs or tissues is reflected in the expression of miRNAs in serum and plasma. Both UC and CD patients had higher blood levels of expressed miR-199a. Long noncoding RNA (lncRNA) ANRIL is a proinflammatory gene that mediates nuclear factor κB to play a role in inflammatory diseases, such as IBD. The aim of the current study is to investigate the potential role of both miR-199a and ANRIL in diagnosing IBD in adult patients. METHODS: Sixty-seven IBD patients diagnosed clinically, radiologically, endoscopically, and histologically were included in this prospective cohort study. Participants were classified into 3 groups: the UC group (n = 35), the CD group (n = 32), and the control group (n = 30). Demographics, history taking, laboratory characteristics, and treatments were recorded. Tumor necrosis factor α, miR-199a, and ANRIL were measured. RESULTS: The findings suggested that miR-199a and ANRIL might be associated with the occurrence or progression of IBD because both genes were substantially expressed in the peripheral blood of patients with this condition. Receiver-operating characteristic curve analysis indicated that the detection of miR-199a and ANRIL had a predictive sensitivity of 62.9% and 88.6% and a specificity of 70.7% and 96.7% for the occurrence of UC cases, respectively, and a predictive sensitivity of 72.4% and 46.9% and a specificity of 96.7% and 34.7% for the occurrence of CD cases, respectively. CONCLUSIONS: Both miR-199a and ANRIL are abundant in the sera of IBD adult Egyptian patients (UC and CD). Both can represent a noninvasive marker for early disease diagnosis.

This study investigated the relation between tumor necrosis factor α, ANRIL, and miR-199a in inflammatory bowel disease patients to determine the probability of using them as prognostic and diagnostic biomarkers, as well as distinguishing between Crohn's disease and ulcerative colitis patients. Our findings showed that ANRIL and miR-199a can represent noninvasive biomarkers for early disease diagnosis.

Dandy-Walker malformation associated with subarachnoid hemorrhage. A case report.

INTRODUCTION: Dandy-Walker malformation is a rare congenital brain defect characterized by vermian agenesia with cystic dilatation of the fourth ventricle, and posterior fossa enlargement. The etiology is still poorly understood but is presupposed to be multifactorial, infrequently caused by intracranial hemorrhage. We describe a case of male newborn known to have Dandy-Walker malformation associated with subarachnoid bleeding after the delivery, which is a quiet rare presentation only discussed in a few literatures before. CASE PRESENTATION: We present a rare case of a full-term male baby delivered vaginally, who was diagnosed with Dandy-Walker malformation during antenatal anomaly scan. At birth, the baby presented with a weak cry, cyanosis, respiratory distress and seizure. Post-delivery computed tomography scan revealed subarachnoid hemorrhage. In addition, a hydrocephalus was noted on the imaging and treated with ventriculoperitoneal shunt insertion with marked improvement of the posterior fossa cyst and the hydrocephalus as an outcome of early intervention. DISCUSSION: Few literature studies showed an association between intracranial bleeding during early fetal life and the development of Dandy-Walker malformation as it affects the posterior fossa components growth. However, our case highlights on an unusual presentation of the spontaneous subarachnoid hemorrhage after the delivery in a full-term baby diagnosed with Dandy-Walker malformation earlier. CONCLUSION: This report highlights the importance of early recognition and implementing appropriate management of the hydrocephalus that associated with intracerebral bleeding to prevent the complications of high intracranial pressure plus brainstem herniation and achieve the best possible outcome.

Glycyrrhizin Enhances the Proliferation of Diabetic Bone Marrow-derived Mesenchymal Stem Cells: A Potential Therapeutic Agent in Endodontic Surgery.

AIM: This study aimed to evaluate the effects of glycyrrhizin, as a potential therapeutic agent in endodontic surgery, on the proliferation and viability of diabetic human bone marrow-derived mesenchymal stem cells (hBM-MSCs). MATERIALS AND METHODS: Diabetic human bone marrow-derived mesenchymal stem cells (hBM-MSCs) were isolated and characterized by flow cytometry. The cells were treated with different concentrations of Glycyrrhizin (Gly) (12.5, 25, 50, and 100 µg/mL) and 0.1% dimethyl sulfoxide (DMSO) as the control group. MTT assay was performed to evaluate the cell proliferation and viability after 24, 48, and 72 hours of the cell treatment with Gly. The optical density (OD) was measured at 570 nm. Each assay was repeated three times. The corrected OD and cell viability were determined. ANOVA followed by the Bonferroni post hoc test evaluated the statistical significance at p < 0.05. RESULTS: Flow cytometric analysis of the isolated cells showed positive expression of mesenchymal markers (CD105 and CD90) and negative expression of hematopoietic markers (CD34 and CD14). After 24 and 48 hours of cell treatment, Gly in 100 µg/mL concentration significantly decreased the diabetic hBM-MSC proliferation as compared with the control (p < 0.05). Gly in 12.5-50 µg/mL concentrations significantly increased the cell proliferation after 72 hours of treatment as compared with the control (p < 0.05). The diabetic hBM-MSC proliferation and viability at 12.5-50 µg/mL concentrations were significantly greater than that at 100 µg/mL concentration (p < 0.05). CONCLUSION: Under the present study conditions, Gly (in 12.5-50 µg/mL concentrations) did not show cytotoxicity to diabetic hBM-MSCs and enhanced their proliferation. Gly may represent a potential therapeutic agent in endodontic surgery in diabetic patients. CLINICAL SIGNIFICANCE: Preclinical assessment of Gly effects on diabetic hBM-MSCs is important for determining its effective concentration range, anticipating its therapeutic potential, and designing future in vivo studies.

Facile Synthesis of Some Coumarin Derivatives and Their Cytotoxicity through VEGFR2 and Topoisomerase II Inhibition.

Novel semisynthetic coumarin derivatives were synthesized to be developed as chemotherapeutic anticancer agents through topoisomerase II, VEGFR2 inhibition that leads to apoptotic cancer cell death. The coumarin amino acids and dipeptides derivatives were prepared by the reaction of coumarin-3-carboxylic acid with amino acid methyl esters following the N,N-dicyclohexylcarbodiimide (DCC) method and 1-hydroxy-benzotriazole (HOBt), as coupling reagents. The synthesized compounds were screened towards VEGFR2, and topoisomerase IIα proteins to highlight their binding affinities and virtual mechanism of binding. Interestingly, compounds 4k (Tyr) and 6c (ß-Ala-L-Met) shared the activity towards the three proteins by forming the same interactions with the key amino acids, such as the co-crystallized ligands. Both compounds 4k and 6c exhibited potent cytotoxic activities against MCF-7 cells with IC50 values of 4.98 and 5.85 µM, respectively causing cell death by 97.82 and 97.35%, respectively. Validating the molecular docking studies, both compounds demonstrated promising VEGFR-2 inhibition with IC50 values of 23.6 and 34.2 µM, compared to Sorafenib (30 µM) and topoisomerase-II inhibition with IC50 values of 4.1 and 8.6 µM compared to Doxorubicin (9.65 µM). Hence, these two promising compounds could be further tested as effective and selective target-oriented active agents against cancer.

Convenient Synthesis of N-Alkyl-2-(3-phenyl-quinoxalin-2-ylsulfanyl)acetamides and Methyl-2-[2-(3-phenyl-quinoxalin-2-ylsulfanyl)acetylamino]alkanoates.

A series of 27 new quinoxaline derivatives (N-alkyl-[2-(3-phenyl-quinoxalin-2-ylsulfanyl)]acetamides, methyl-2-[2-(3-phenylquinoxalin-2-ylsulfanyl)-acetylamino]alkanoates, and their corresponding dipeptides) were prepared from 3-phenylquinoxaline-2(1H)-thione based on the chemoselective reaction with soft electrophiles. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to study the efficacy of 27 compounds on cancer cell viability and proliferation. A total of 13 compounds (4a-c, 5, 6, 8c, 9c, 9f, 10a, 10b, 11c, 12b, and 12c) showed inhibitory action on HCT-116 cancer cells and 15 compounds (4a-c, 5, 6, 8c, 9a, 9c, 9f, 9h, 10b, 11c, 12a, 12b, and 12c) showed activity on MCF-7 cancer cells, with compound 10b exhibiting the highest inhibitory action (IC50 1.52 and 2 µg/mL, respectively) on both cell lines. The molecular modeling studies on the human thymidylate synthase (hTS) homodimer interface showed that these compounds are good binders and could selectively inhibit the enzyme by stabilizing its inactive conformation. The study also identified key residues for homodimer binding, which could be used for further optimization and development.

Experimental and Theoretical Investigation of the Thermophysical Properties of Cobalt Oxide (Co3O4) in Distilled Water (DW), Ethylene Glycol (EG), and DW-EG Mixture Nanofluids.

Solid particles scattered in a base fluid for a standard no larger than 100 nm, constituting a nanofluid, can be used to improve thermophysical characteristics compared to the base fluid. In this study, theoretical and experimental investigations were carried out to estimate the density, viscosity, and effective thermal conductivity of Co3O4 in distilled water (DW), ethylene glycol (EG), and DW-EG mixture nanofluids. Co3O4 nanoparticles with diameters of 50 nm were dispersed in different base fluids (i.e., EG, DW, 60EG:40DW, 40EG:60DW, 20EG:80DW) with varying concentrations of 0.025-0.4 vol.%. Thermal conductivity was estimated by the hot-wire technique, and viscosity was determined using a viscometer apparatus. According to the measurements, the viscosity of Co3O4 nanofluids decreased with increasing temperature, and increased with increasing volume fraction. The results revealed that the thermal conductivity of Co3O4 nanofluids increased with increasing temperature and volume concentrations. Moreover, the measurements found that the maximum thermal conductivity of 10.8% and the maximum viscosity of 10.3% prevailed at 60 °C in the volume fraction of 0.4%. The obtained viscosity and thermal conductivity results of the present experiments on Co3O4 nanofluids were compared with previous results. The results showed good agreement with theoretically proposed models to predict nanofluids' viscosity and thermal conductivity. Thus, the thermal conductivity results of Co3O4 nanofluids are promising with respect to the use of nanofluids in solar thermal applications.

Valorization of whey proteins and beetroot peels to develop a functional beverage high in proteins and antioxidants.

Introduction: Adequate protein and antioxidant intake are crucial for everyone, particularly athletes, to promote muscle performance and prevent muscle damage. Whey proteins are high-quality proteins with high digestibility and bioavailability; beetroot peels are an abundant antioxidant source. Methods: The present study was designated to develop a functional beverage based on mixing whey protein isolate (5%) with different concentrations of beetroot peel water extract (1, 2.5, and 5%) and flavored with strawberries puree (5%). In addition, we examined the stability of the physicochemical parameters and the bioactive components of the beverages during cold storage (4°C) for 14 days. Results and discussion: Whey protein isolates enriched the juices with stable protein content during the storage (4.65-4.69%). Besides, the extract revealed a concentration-dependent effect on the bioactive components, the antioxidant activity, and the microbial load of the juices; it distinguished the fresh juices by high betalains and nitrate content, 87.31-106.44 mg/L and 94.29-112.59 mg/L, respectively. Beverages with 2.5% peel extract (T2) had the preferable sensory attributes compared to control and other treatments. On day 0, phenolics and flavonoids increased in T2 by 44 and 31% compared to the control, which elevated the scavenging activity of the juice (T2) (P < 0.05). At the end of the storage period (14 days), phenolics and flavonoids of T2 recorded their lowest values, 26.23 and 21.75 mg/mL, respectively. However, they stood higher than phenolics (22.21 mg/mL) (p < 0.05) and flavonoids (18.36 mg/mL) (p > 0.05) of control. Similarly, betalains degraded by 45% to reach 47.46 mg/L in T2, which reduced the redness (a*) and increased the yellowness (b*) values. Conclusion: Consequently, whey/strawberry/beetroot peel (5: 5: 2.5 w/v/w) in d.H2O is a functional beverage that provides the body with a high-quality protein and a considerable amount of antioxidants.

Synthesis and Cytotoxic Activity of Novel Metal Complexes Derived from Methyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate as Potential CDK8 Kinase Inhibitors.

Several metal complexes of methyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate derivatives were synthesized and tested for their anti-tumor activities. The ligands include 3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoic acid (1), 3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanehydrazide (2), and 3-(4-chlorophenyl)-N'-(4-(dimethylamino)benzylidene)-3-hydroxy-2,2-dimethylpropanehydrazide (3). The ligands were reacted with Cu (II), Ni (II), and La (III) ions. The formed complexes were characterized using elemental analysis (M%), molar conductivity in DMF (0.001 M), DTA, TG, FTIR, ICP-AES, and magnetic susceptibility. The chemical structures of the obtained complexes were interpreted, and their chemical formulas were postulated. The anti-cancer activities of these complexes were examined on human colorectal carcinoma cells (HCT-116) and also on normal cells (HEK-293). The 48 h post treatments showed that out of 12 compounds, 10 compounds showed inhibitory actions on HCT-116 cells, whereas two compounds did not show any inhibitory actions. Compounds 6c and 4a showed the highest inhibitory actions with IC50 = 0.154 and 0.18 mM and additionally compounds 3, 4b, and 6a with IC50 = 0.267, 0.205, and 0.284 mM, respectively. All tested compounds did not show any inhibitory action on normal HEK-293 cells. Molecular docking results provided a good evidence for activity of the lead compounds 3 and 4a as CDK8-CYCC kinase inhibitors, which may proposed the mechanism of action toward colon cancer therapy.

Shaping ability of three thermally treated nickel-titanium systems in S-shaped canals.

This study aimed to compare the shaping ability of ProTaper Next (PTN), HyFlex EDM (HEDM) and One Curve (OC) systems manufactured via different thermal treatment methods in simulated S-shaped canals. Sixty S-shaped canals in clear resin blocks were enlarged to a final apical size of 25 using PTN, HEDM and OC instruments (n = 20 canals/group). Composite images were obtained by superimposing pre- and post-preparation images. The amount of removed resin was measured perpendicularly to the canal surface in 22 points. Prepared canal width and canal transportation at different levels were determined. Canal aberrations were also recorded. Data were statistically analysed using analysis of variance, the Kruskal-Wallis and the chi-square tests at a 0.05 significance level. OC produced the most conservative enlargement and better maintained particularly the apical curvature of the S-shaped canals than HEDM and PTN. OC and HEDM better maintained the canal terminus and coronal curvature than PTN.

In depth investigation of the retention behavior of structurally related ß-blockers on RP-HPLC column: Quality by design and quantitative structure-property relationship complementary approaches for optimization and validation.

The persistent introduction of new ß-blockers motivates the demand for optimizing RP-HPLC well-designed analytical procedures that could be applied to this structurally related and commonly prescribed pharmacological group in order to reduce time and chemicals consumption in quality control units. Betoxolol HCl (BEX) and Carvidolol (CAR) were selected as representative examples to conduct predictive studies based on two complementary approaches, Quality by design (QBD) and Quantitative structure property relationship (QSPR). In concern QBD, a Box-Behnken design was adopted at variable chromatographic parameters to achieve the most proper conditions that might be applied for efficient analysis of the majority of group members. On the other hand, the retention time was chosen as the target property in the QSPR study that was conducted onto seven ß. blockers (the two investigated drugs in addition to five other ß. blockers) to find the best correlated molecular descriptors to the retention behavior. Both external and internal validation studies have comparable quality with training levels. Hence a simple selection algorithm of conventional features provides robust confirmatory predictive QBD and QSPR models. Derringer's desirability function as as a multi-criteria approach was applied for getting the optimum chromatographic analysis conditions. Efficient analysis of BET and CAR was achieved at column temperatures of 26.00 and 27.50 °C, respectively using acetonitrile and phosphate buffer (pH 4.55) 70:30 v/v as a mobile phase with a flow rate of 1.00 mL/min, and UV detection at 220 nm. The method was validated in accordance to ICH guidelines, and had exhibited acceptable precision, accuracy, linearity, and robustness.

Characteristics and predictors of burnout among healthcare professionals: a cross-sectional study in two tertiary hospitals.

BACKGROUND: The pattern and impact of burnout among the medical staff are not yet well defined. However, the consequences of burnout are not limited to the healthcare providers but also may affect their family, colleagues and patients in a negative manner. We aimed to assess the characteristics and predictors of burnout among health professionals at two large tertiary hospitals. METHODS: We conducted a cross-sectional study during the period from July 2018 to 31 December 2018. Data, via Maslach Burnout Inventory survey, were collected from physicians and other healthcare workers in two hospitals. RESULTS: A total of 624 responses to questionnaires were analysed. Half of the respondents were physicians, and men constituted the majority. About 10% (95% CI, 7.8 to 12.5) of the respondents satisfied the criteria of burnout. Emotional exhaustion (EE) was observed in 45.7%, depersonalisation (DP) in 26.9% and personal accomplishment (PA) in 41.2% of the respondents. There was a positive correlation between EE and DP (r=0.627, p=0.001), and a weak negative correlation between DP and PA (r=-0.195, p=0.001). Young age, less experience, trauma surgery, lack of habits and getting depressed ≥1 time/week were predictors of burnout. CONCLUSIONS: Burnout affects one-tenth of the health professionals in the tertiary hospitals in Qatar. Physicians are more likely to have higher DP and lower PA, whereas nurses prone to have higher EE. In this study, no gender discrepancy is appreciated and the junior medical staff is at a higher risk of burnout.

Outcome of idiopathic intracranial hypertension after laparoscopic sleeve gastrectomy.

BACKGROUND: Idiopathic intracranial hypertension (IIH) predominantly affects young, obese women and presents with signs and symptoms of increased intracranial pressure, such as headaches and visual impairment. OBJECTIVE: We aim to present our experience in the management of IIH. SETTING: University Hospital. METHODS: Obese IIH patients who had a laparoscopic sleeve gastrectomy during the study period (2 years) were included. Data were retrieved from prospectively collected database. Headaches, visual alterations, and medications or interventions used to treat are discussed. RESULTS: The study included 16 obese women with IIH. Mean age was 31 ± 2 years (range, 25-44 yr) and mean body mass index was 46 ± 4 kg/m2 (range, 42-53 kg/m2). Main symptoms and signs were chronic headaches (14), impaired vision (15), vision loss (1), papilledema (6), and field defects in 4 patients. Symptoms were present for a mean of 5 years (4-11). History of medical treatment with carbonic anhydrase inhibitor (acetazolamide) and thecoperitoneal shunting was present in 12 and 9 patients, respectively. Mean lumbar puncture opening pressure was 41.2 ± 21- (range, 30-64) cm water. At 12 months after laparoscopic sleeve gastrectomy, body mass index and percentage excess weight loss were 27.8 ± 1 kg/m2 and 75.2 ± 2%, respectively. Symptoms gradually improved with complete resolution in all but 2 patients (87.5%). CONCLUSION: The present work emphasizes the role of bariatric surgery in the management of obese patients with IIH. Larger, prospective, controlled studies are needed.

Use of algal biorefinery waste and waste office paper in the development of xerogels: A low cost and eco-friendly biosorbent for the effective removal of congo red and Fe (II) from aqueous solutions.

The present study investigated the use of algae biorefinery waste and wastepaper in the preparation of cost-effective and eco-friendly xerogels for the removal of congo red (CR) and Fe2+. The xerogel properties such as density, swelling degree and porosity were modified by incorporating alginate extracted from the brown seaweed Cystoseira trinodis. The developed biosorbents exhibited a light and porous network structure and were characterized by a fast uptake of CR and Fe2+ and adsorption efficiency was increased at pH 6-8. The equilibrium adsorption capacity was found to be 6.20-7.28 mg CR g-1 biosorbent and 8.08-8.39 mg Fe2+ g-1 biosorbent using different xerogels. The adsorption of CR obeyed first-order kinetics, while, Fe2+ followed second-order kinetics. Intraparticle diffusion model suggested a boundary layer effect. The adsorption capacity was maximally obtained as 41.15 mg g-1 and 169.49 mg g-1 for CR and Fe2+ using wastepaper/Spirulina and wastepaper/alginate/Spirulina xerogel, respectively. Temkin isotherm fitted better to the equilibrium data of CR adsorption than Langmuir and Freundlich models. While, equilibrium data of Fe2+ exhibited a best fit to both Langmuir and Freundlich models. Additionally, the Dubinin-Radushkevich isotherm suggested that adsorption mechanism of CR or Fe2+ is predominately physisorption. Investigation of thermodynamic parameters such as ΔH° and ΔS° and ΔG° confirmed the feasibility, spontaneity, randomness and endothermic nature of the adsorption process. Electrostatic attraction, H-bonding and n-π interactions were mainly involved in the biosorption process of CR. The results of this study showed that the developed xerogels could be effectively applied for dye and heavy metal removal at low concentrations.

Newly synthesized 3-(4-chloro-phenyl)-3-hydroxy-2,2-dimethyl-propionic acid methyl ester derivatives selectively inhibit the proliferation of colon cancer cells.

A series of 24 compounds were synthesized based on structure modification of the model methyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate as potent HDACIs. Saponification and hydrazinolysis of the model ester afforded the corresponding acid and hydrazide, respectively. The model ester was transformed into the corresponding trichloroacetimidate or acetate by the reaction with trichloroacetonitrile and acetic anhydride, respectively. N-Alkyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropan-amides and methyl-2-[(3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoyl)amino] alkanoates were obtained by the reaction of corresponding acid or hydrazide with amines and amino acid esters via DCC and azide coupling methods. Methyl-3-aryl-3-(4-chlorophenyl)-2,2-dimethylpropanoates were obtained in good yields and short reaction time from the corresponding trichloroacetimidate or acetate by the reaction with C-active nucleophiles in the presence of TMSOTf (0.1 eq.%) via C-C bond formation. The antiproliferative and apoptotic activity were further studied with molecular docking. The 48 post-treatments showed that out of 24 compounds, 12 compounds showed inhibitory actions on HCT-116 cells, we have calculated the inhibitory action (IC50) of these compounds on HCT-116 and we have found that the IC50 values were in between 0.12 mg mL-1 to 0.81 mg mL-1. The compounds (7a & 7g) showed highest inhibitory activity (0.12 mg mL-1), whereas compound 7d showed the lowest inhibitory activity (0.81 mg mL-1). We have also examined inhibitory action on normal and non-cancerous cells (HEK-293 cells) and confirmed that action of these compounds was specific to cancerous cells. The cancerous cells were also examined for nuclear disintegration through staining with DAPI, (4',6-diamidino-2-phenylindole) is a blue-fluorescent DNA stain, and we have found that there was loss of DAPI staining in the compound treated cancerous cells. The compounds were found to potentially act through the HSP90 and TRAP1 mediated signaling pathway. Compounds 7a and 7g showed the highest selectivity to TRAP1 which explained its superior activity.

Synthesis and Anti-Proliferative Assessment of Triazolo-Thiadiazepine and Triazolo-Thiadiazine Scaffolds.

A series of triazolo-thiadiazepines 4a-k were synthesized with excellent yields using dehydrated PTSA as a catalyst in toluene. Two triazolo-thiadiazines were obtained; 8a was formed directly by reflux in ethanol, whereas, PTSA promoted the formation of 8b. The molecular structure of the formed triazolo-thiadiazepines is identical to the imine-form 4a-k and not the enamine-tautomer 6a-k. The structures of the newly synthesized triazolo-thiadiazepines 4a-k and triazolo-thiadiazines 8a-b were elucidated using NMR (1H, and 13C), 2D NMR, HRMS, and X-ray single crystal. Furthermore, 4a was deduced using X-ray single crystal diffraction analysis. These new thiadiazepine hits represent an optimized series of previously synthesized indole-triazole derivatives for the inhibition of EGFR. The cytotoxicity activity against two cancer cell lines including human liver cancer (HEPG-2) and breast cancer (MCF-7) was promising, with IC50 between 12.9 to 44.6 µg/mL and 14.7 to 48.7 µg/mL for the tested cancer cell lines respectively, compared to doxorubicin (IC50 4.0 µg/mL). Docking studies revealed that the thiadiazepine scaffold presented a suitable anchor, allowing good interaction of the various binding groups with the enzyme binding regions and sub-pockets.

Convenient Synthesis and Anticancer Activity of Methyl 2-[3-(3-Phenyl-quinoxalin-2-ylsulfanyl)propanamido]alkanoates and N-Alkyl 3-((3-Phenyl-quinoxalin-2-yl)sulfanyl)propanamides.

A series of methyl 2-[3-(3-phenyl-quinoxalin-2-ylsulfanyl)propanamido]alkanoates and their corresponding hydrazides and N-alkyl 3-((3-phenylquinoxalin-2-yl)sulfanyl)propanamides were prepared on the basis of the chemoselective Michael reaction of acrylic acid with the parent substrate 3-phenylquinoxaline-2(1H)-thione. The parent thione was produced by a convenient novel thiation method from the corresponding 3-phenylquinoxalin-2(1H)-one. The chemical structures of the newly synthesized compounds were confirmed by elemental analyses, 1H and 13C NMR. The antiproliferative activity of the synthesized compounds was tested against human HCT-116 and MCF-7 cell lines. Out of 25 screened derivatives, 10 active compounds exhibited IC50's in the range 1.9-7.52 µg/mL on the HCT-116, and 17 active compounds exhibited IC50's in the range 2.3-6.62 µg/mL on the MCF-7 cell lines compared to the reference drug doxorubicin (IC50 3.23 µg/mL). The structure-activity relationship of the tested compounds was studied through their binding affinity to the human thymidylate synthase allosteric site in silico using molecular docking and proved the quinoxaline ring as a suitable scaffold carrying a peptidomimetic side chain in position 3.

Design and synthesis of new phthalazine-based derivatives as potential EGFR inhibitors for the treatment of hepatocellular carcinoma.

Searching for new leads in the battle of cancer will never ends, we herein disclose the design and synthesis of new phthalazine derivatives and their in vitro and in vivo testing for their antiproliferative activity. Phthalazine was selected as a privilege moiety that is incorporated in a big number of anticancer drugs in clinical use or that are still under clinical or preclinical studies. We utilized the drug extension strategy to tailor the designed compounds to fit the EGFR hydrophobic sub pocket and cleft region. The designed phthalazine derivatives was synthesized by linking phthalazine moiety with 1,3,4-oxadiazole-thione and 1,2,4-triazole-thione. Alkylation and glycosylation of the new heterocyclic systems were successfully performed to be used in the drug extension. Coupling of some phthalazine derivatives with different amino acids was also performed to improve the drug selectivity. The synthesized compounds were tested for their antiproliferative activity against cancer cells both in vivo and in vitro. The in vitro activity against hepatocellular carcinoma (HepG2 cell line) ranged from 5.7 µg/mL to 43.4 µg/mL. Compounds 31a and 16 were the most active with an IC50 5.7 µg/mL and 7.09 µg/mL, respectively compared to the standard compound doxorubicin (4.0 µg/mL). In vivo, compounds 10 and 16 showed IC50 values 7.25 µg/mL and 7.5 µg/mL, respectively compared to the standard compound cisplatin (IC50 9.0 µg/mL). In silico, testing of the phthalazine derivatives showed that they are good inhibitors for EGFR. The docking studies substantiated compounds 4, 10, 16 and 31a as new lead compounds and identified Arg841 as a key residue in the cleft region for binding stronger inhibitors.

Amelioration of experimental metabolic syndrome induced in rats by orlistat and Corchorus olitorius leaf extract; role of adipo/cytokines.

OBJECTIVES: To determine the efficacy of Corchorus olitorius (C. olitorius) leaf extract in the prevention of metabolic syndrome induced in rats by high-fat diet (HFD) and compare it with that of orlistat. METHODS: Phytochemical analysis was performed. Effect of orlistat and C. olitorius extract on lipase activity and acute food intake were investigated. Body weight, biochemical parameters and histopathological examination were demonstrated. KEY FINDINGS: Corchorus olitorius extract inhibited the pancreatic lipase activity, but orlistat was more potent. Cumulative food intake has not changed by the tested agents. In obese rats, C. olitorius or orlistat significantly decreased weight gain and visceral white adipose tissue. They exhibited a significant reduction in serum glucose, total cholesterol, triglycerides, low density lipoprotein cholesterol, free fatty acids, IL-1ß, tumour necrosis factor-α (TNF-α), insulin and leptin levels of obese rat groups while high density lipoprotein cholesterol and adiponectin levels were significantly increased by them. Histopathological examination of the liver revealed that C. olitorius was more effective than orlistat in the alleviating of steatosis and adipocyte hypertrophy shown in obese control rats. CONCLUSIONS: Corchorus olitorius is effective as orlistat in preventing obesity, hyperlipidaemia, steatosis and insulin resistance. These actions may be mediated by inhibiting of lipase activity, TNF-α, IL-1ß and leptin resistance along with increasing of adiponectin.

Bone health consequence of adjuvant Anastrozole in monotherapy or associated with biochanin-A in ovariectomized rat model.

AIMS: We investigate the consequence of adjuvant anastrozole (ANA) in monotherapy or associated with biochanin A (BCA) in ovariectomized (OVX) rat model and the degree of developing bone loss in both conditions. MATERIALS AND METHODS: Sixty female rats were assigned to six groups. Five groups were bilaterally OVX, and one was sham operated. The five groups were; ANA group (0.5 mg/kg b.wt orally), BCA (5 mg/kg b.wt intraperitoneally (I/P), co-treated group (BCA + ANA), two control groups receiving even distilled water orally or DMSO I/P for twenty weeks. Bone turnover biomarkers BALP, OC, PTH, TRAP and TNFα were determined in serum. Bone mineral content, histological and morphometric measurements on rat femurs were performed. BMD by X-ray technique on tibias of rats and CT analysis of lumbar vertebrae of all treated and sham groups were applied. KEY FINDINGS: There was marked elevation in bone turnover biomarkers with high serum Ca and P content in the ANA-treated rats. Moreover marked elevation of TNFα, PTH, TC and TG, ANA caused severe changes in the BMD detected by X-ray in tibial bones and CT analysis of lumbar vertebrae of OVX rats. While I/P injection of BCA ameliorated the adverse bone health decrements caused by ANA. SIGNIFICANCE: The study highlights the importance of the BCA supplementation in accordance with the ANA therapy in case of ovariectomized rat model of osteoporosis which is clinically presented in Postmenopausal women with breast cancer during which considerable risk of developing osteoporosis is predicted during treatment.