Search

To genotype healthy Jordanian population from three different provinces (Amman, Zarqa and Irbid) for cytochrome P4502C19 and to identify the allelic distribution of CYP2C19 variants in comparison with other findings around the world. Methods: Healthy Jordanian volunteers were recruited from government hospitals. Two hundred and sixty volunteers were included in the study regardless of sex and age. CYP2C19*2, *3,*4, *5, and *6 alleles were studied using polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP) technique. Results: The results show that the Jordanian population tested exhibited 9 genotypes out of the 21 expected CYP2C19 genotypes. CYP2C19*1/*1 and *2/*2 genotypes were the most prominent in the sample population, while CYP2C19*2/*5 was the least prevalent genotype. The frequencies of the CYP2C19 variants did not deviate from Hardy-Weinberg equilibrium. Allele frequency of CYP2C19*2 in the Jordanian population was statistically different from that found in most Europeans, North and South Americans, Africans, and some Asian ethnic communities but not with South-East Asian populations (China, Chinese-Taiwanese, and Philippines) and Australian Aborigines. Conclusion: The findings of this study confirm the importance of CYP2C19 genotyping prior to drug therapy administration to achieve optimal dosage and cost-effective therapy. [ABSTRACT FROM AUTHOR]

cis-Dichloro-palladium(II) and cis-dichloro-platinum(II) complexes (2, 4) of the general formula [M(N-N)Cl2] (M=Pd(II) and Pt(II), N-N= 1,2-diamino-4-fluoro-5-(4-methyl-1-piperazinyl) benzene, (DFMPB)) and the dicationic palladium(II) complex [Pd(N-N)(CH3CN)2](BF4)2 (3) have been prepared and characterized by elemental analysis, 1H-NMR-, mass spectroscopy, and IR spectroscopy. The cytotoxic effect of these complexes against MDA-231 and MCF-7 human breast cancer cell lines and K562 human leukemia cell line has been studied. The influence was dose dependent and varies with cell type. The palladium(II) complex (2) showed superior cytotoxic effect compared with the corresponding platinum(II) complex and the standard, cisplatin, when tested against all the above cell lines. [ABSTRACT FROM AUTHOR]

The effect of total body glutathione (GSH) depletion induced by L-buthionine-(S,R)-sulfoximine (BSO) treatment on the murine immune system has not been studied previously. BSO was administered via drinking water for 14 days to induce total body GSH depletion. A significant decrease in total GSH (TGSH) of the immune organs such as spleen, liver, peritoneal macrophages as well as blood was observed. The proliferative response of splenocytes against different types of mitogens was significantly decreased in GSH-depleted mice compared to controls. The expression of several antioxidant enzymes was studied in both treated and control mice. No significant change was seen in major antioxidant enzymes; manganese superoxide dismutase and catalase. However, the expression of heme oxygenase-1 was increased in both liver and spleen in BSO-treated mice. Total body GSH depletion also increased lipid peroxidation as demonstrated by higher levels of malondialdehyde in BSO-treated mice. All the above-mentioned changes were reversed to near normal 14 days post termination of BSO treatment. These results demonstrate that TGSH depletion induces oxidative stress and adversely affects the function of the murine immune system. [ABSTRACT FROM AUTHOR]

2DG causes cytotoxicity in cancer cells by disrupting thiol metabolism while Doxorubicin (DOX) induces cytotoxicity in tumor cells by generating reactive oxygen species (ROS). Here we examined the combined cytotoxic action of 2DG and DOX in rapidly dividing T47D breast cancer cells vs. slowly growing MCF-7 breast cancer cells. T47D cells exposed to the combination of 2DG/DOX significantly decreased cell survival compared to controls, while 2DG/DOX had no effect on MCF-7 cells. 2DG/DOX also disrupted the oxidant status of T47D treated cells, decreased intracellular total glutathione and increased glutathione disulfide (%GSSG) compared to MCF-7 cells. Lipid peroxidation increased in T47D cells treated with 2DG and/or DOX, but not in MCF-7 cells. T47D cells were significantly protected by NAC, indicating that the combined treatment exerts its action by increasing ROS production and disrupting antioxidant stores. When we inhibited glutathione synthesis with BSO, T47D cells became more sensitive to 2DG/DOX-induced cytotoxicity, but NAC significantly reversed this cytotoxic effect. Finally, 2DG/DOX, and BSO significantly increased the %GSSG in T47D cells, an effect which was also reversed by NAC. Our results suggest that exposure of rapidly dividing breast cancer cells to 2DG/DOX enhances cytotoxicity via oxidative stress and via disruptions to thiol metabolism. [ABSTRACT FROM AUTHOR]

A new cetyl‐alcohol‐reinforced hollow fiber solid/liquid‐phase microextraction (CA–HF–SLPME) followed by high‐performance liquid chromatography–diode array detection (HPLC–DAD) method was developed for simultaneous determination of ezetimibe and simvastatin in human plasma and urine samples. To prepare the CA–HF–SLPME device, the cetyl‐alcohol was immobilized into the pores of a 2.5 cm hollow fiber micro‐tube and the lumen of the micro‐tube was filled with 1‐octanol with the two ends sealed. Afterwards, the prepared device was introduced into 10 mL of the sample solution containing the analytes with agitation. Under optimized conditions, calibration curves plotted in spiked plasma and urine samples were linear in the ranges of 0.363–25/0.49–25 μg L−1 for ezetimibe/simvastatin and 0.193–25/0.312–25 μg L−1 for ezetimibe/simvastatin in plasma and urine samples, respectively. The limit of detection was 0.109/0.174 μg L−1 for ezetimibe/simvastatin in plasma and 0.058/0.093 μg L−1 for ezetimibe/simvastatin in urine. As a potential application, the proposed method was applied to determine the concentration of selected analytes in patient plasma and urine samples after medication and satisfactory results were achieved. In comparison with reference methods, the CA–HF–SLPME–HPLC–DAD method demonstrates considerable potential in the biopharmaceutical analysis of selected drugs. [ABSTRACT FROM AUTHOR]

Introduction/background: Because of the well-established link between angiogenesis and tumor development, the use of antiangiogenic therapeutics, such as those targeting VEGFR-2, presents a promising approach to cancer treatment. In the current study, a set of five hydrazine-1-- carbothioamide (compounds 3a-e) and three hydrazine-1-carboxamide derivatives (compounds 4a-c) were successfully synthesized from 3-phenoxybenzoic acid. These compounds were specially created as antiproliferative agents with the goal of targeting cancer cells by inhibiting VEGFR-2 tyrosine kinase., Materials and Methods: The new derivatives were synthesized by conventional organic methods, and their structure was versified by IR, 1HNMR, 13CNMR, and mass spectroscopy. In silico investigation was carried out to identify the compounds' target, molecular similarity, ADMET, and toxicity profile. The cytotoxic activity of the prepared compounds was evaluated in vitro against three human cancer cell lines (DLD1 colorectal adenocarcinoma, HeLa cervical cancer, and HepG2 hepatocellular carcinoma). The effects of the leading compound on cell cycle progression and apoptosis induction were investigated by flow cytometry, and the specific apoptotic pathway triggered by the treatment was evaluated by RT-PCR and immunoblotting. Finally, the inhibitory activities of the new compounds against VEGFR-2 was measured., Results: The designed derivatives exhibited comparable binding positions and interactions to the VEGFR-2 binding site to that of sorafenib (a standard VEGFR-2 tyrosine kinase inhibitor), as determined by molecular docking analysis. Compound 4b was the most cytotoxic compound, achieving the lowest IC50 against HeLa cells. Compound 4b, a strong representative of the synthesized series, induced cell cycle arrest at the G2/M phase, increased the proportion of necrotic and apoptotic HeLa cells, and activated caspase 3. The EC50 value of compound 4b against VEGFR-2 kinase activity was comparable to sorafenib's., Conclusion: Overall, the findings suggest that compound 4b has a promising future as a starting point for the development of new anticancer drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Allosteric inhibition of EGFR tyrosine kinase (TK) is currently among the most attractive approaches for designing and developing anti-cancer drugs to avoid chemoresistance exhibited by clinically approved ATP-competitive inhibitors. The current work aimed to synthesize new biphenyl-containing derivatives that were predicted to act as EGFR TK allosteric site inhibitors based on molecular docking studies., Methods: A new series of 4'-hydroxybiphenyl-4-carboxylic acid derivatives, including hydrazine-1-carbothioamide (S3-S6) and 1,2,4-triazole (S7-S10) derivatives, were synthesized and characterized using IR, 1 HNMR, 13 CNMR, and HR-mass spectroscopy., Results: Compound S4 had a relatively high pharmacophore-fit score, indicating that it may have biological activity similar to the EGFR allosteric inhibitor reference, and it scored a relatively low ΔG against EGFR TK allosteric site, indicating a high likelihood of drug-receptor complex formation. Compound S4 was cytotoxic to the three cancer cell lines tested, particularly HCT-116 colorectal cancer cells, with an IC 50 value comparable to Erlotinib. Compound S4 induced the intrinsic apoptotic pathway in HCT-116 cells by arresting them in the G2/M phase. All of the new derivatives, including S4, met the in silico requirements for EGFR allosteric inhibitory activity., Conclusion: Compound S4 is a promising EGFR tyrosine kinase allosteric inhibitor that warrants further research., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Since the discovery of cephalostatins, which have shown remarkable activity against human cancer cells, they have attracted the attention of researchers to target the synthesis of such impressive, complicated molecules using the green desymmetrization approach. In the current review, we report the progress in the desymmetrization of symmetrical bis-steroidal pyrazines (BSPs) as an approach toward potentially active anti-- cancer agents, namely cephalostatins/ ritterazines. The achievement of synthesizing a gram-scaled prodrug with comparable activity to the potent natural cephalostatins using green methods is our primary target. These synthetic methods can be scaled up based on the symmetrical coupling (SC) of two steroidal units of the same type. Our secondary target is the discovery of new green pathways that help in structural reconstruction programming toward the total synthesis of at least one potentially active family member. The strategy is based on functional group interconversions with high flexibility and brevity using green selective methods. The introduction of controlling groups using nontrivial reconstruction methodologies forms the backbone of our work. After certain modifications to the symmetrical BSP starting material, the resulting analogs underwent several chemoselective transformations through three main routes in rings F, D, and C. One of these routes is the chemoselective spiroketal opening (ring-F). The second route was the functionalization of the Δ14,15 bond (ring-D), including chlorination/dechlorination, in addition to epoxidation/ oxygenation processes. Finally, the introduction of the C-11 methoxy group as a directing group on ring-C led to several chemoselective transformations. Moreover, certain transformations on C-12 (ring-C), such as methylenation, followed by hydroboration- oxidation, led to a potentially active analog. The alignment of these results directs us toward the targets. Our efforts culminated in preparing effective anti-cancer prodrugs (8, 24, 30, and 31), which are able to overcome cancer drug resistance (chemoresistance) by inducing the atypical endoplasmic reticulum-mediated apoptosis pathway, which works through the release of Smac/Diablo and the activation of caspase-4., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: 1,3,4-oxadizole and pyrazole derivatives are very important scaffolds for medicinal chemistry. A literature survey revealed that they possess a wide spectrum of biological activities including anti-inflammatory and antitumor effects., Objectives: To describe the synthesis and evaluation of two classes of new niflumic acid (NF) derivatives, the 1,3,4-oxadizole derivatives (compounds 3 and (4A-E) and pyrazole derivatives (compounds 5 and 6), as EGFR tyrosine kinase inhibitors in silico and in vitro., Methods: The designed compounds were synthesized using conventional organic synthesis methods. The antitumor activities of the new NF derivatives against HepG2 hepatocellular carcinoma and A549 non-small cell lung cancer cell lines were assessed in vitro via MTT assay, flow cytometry, RT-PCR, as well as via molecular docking studies., Results: The cytotoxicity results indicated that the newly synthesized NF derivatives were cytotoxic against the two cancer cell lines, with compound 6 being the most cytotoxic, achieving the lowest IC 50 concentration. Furthermore, compound 6 targeted EGFR tyrosine kinase leading to cell cycle arrest at the G2/M cell cycle phase and induction of apoptosis. The in vitro biological investigation results matched those of the molecular docking analysis. In conclusion, the new NF derivatives, specifically compound 6, exhibited favorable pharmacokinetic features and are promising EGFR tyrosine kinase inhibitors., Conclusion: A series of niflumic acid derivatives (3, 4A-E, 5, and 6) were successfully created, and FT-IR, ^{1H, ₁₃CNMR, and HRMS were used to confirm their chemical structures. According to molecular docking studies, compounds 3, 5, and 6 have the highest docking scores (ΔG), and most tested compounds have a good pharmacokinetic profile. Results of compound 6 in vitro antitumor activities showed that it is a promising EGFR tyrosine kinase inhibitor., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)}

Background: The indole backbone is encountered in a class of N-heterocyclic compounds with physiological and pharmacological effects such as anti-cancer, anti-diabetic, and anti-HIV. These compounds are becoming increasingly popular in organic, medicinal, and pharmaceutical research. Nitrogen compounds' hydrogen bonding, dipole- dipole interactions, hydrophobic effects, Van der Waals forces, and stacking interactions have increased their relevance in pharmaceutical chemistry due to their improved solubility. Indole derivatives, such as carbothioamide, oxadiazole, and triazole, have been reported to act as anti-cancer drugs due to their ability to disrupt the mitotic spindle and prevent human cancer cell proliferation, expansion, and invasion., Objectives: To synthesize new 5-bromoindole-2-carboxylic acid derivatives that function as EGFR tyrosine kinase inhibitors as deduced through molecular docking studies., Methods: Different derivatives of indole (carbothioamide, oxadiazole, tetrahydro pyridazine-3,6-dione, and triazole) were synthesized and evaluated through different chemical, spectroscopic methods (IR, 1 HNMR, 13 CNMR, and MS) and assessed in silico and in vitro for their antiproliferative activities against A549, HepG2, and MCF-7 cancer cell lines., Results: According to molecular docking analyses, compounds 3a, 3b, 3f, and 7 exhibited the strongest EGFR tyrosine kinase domain binding energies. In comparison to erlotinib, which displayed some hepatotoxicity, all of the evaluated ligands displayed good in silico absorption levels, did not appear to be cytochrome P450 inhibitors, and were not hepatotoxic. The new indole derivatives were found to decrease cell growth of three different types of human cancer cell lines (HepG2, A549, and MCF-7), with compound 3a being the most powerful while still being cancer-specific. Cell cycle arrest and the activation of apoptosis were the results of compound 3a's inhibition of EGFR tyrosine kinase activity., Conclusion: The novel indole derivatives, compound 3a in particular, are promising anti-cancer agents which inhibit cell proliferation by inhibiting EGFR tyrosine kinase activity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Taraxacum officinale has been used in Jordan folk medicine to treat male infertility. A recent study has proved a contradictory effect of the whole plant aqueous extract. The aim of the current study was to determine if the leaves of T. officinale have similar anti-fertility activities, and whether this effect is mediated through the regulation of spermatogonial stem cells (SSCs). Fifty adult male rats were divided into five groups. Two groups were gavaged with 1/10 of LD50 of T. officinale whole plant (1.06 g kg(-1) body weight) or leaves (2.30 g kg(-1) body weight) aqueous extract; while two groups were gavaged with 1/20 of LD50 of T. officinale whole plant (2.13 g kg(-1)) or leaves (4.60 g kg(-1)) extract. The control group received distilled water. Oral administration of T. officinale (whole plant and leaves aqueous extract) caused a significant decrease in testis and seminal vesicle weight, a reduction in serum testosterone concentration, impaired sperm parameters, and a decrease in pregnancy parameters. Testicular histology of treated rats showed structural changes such as hypoplasia of germ cells, reduction in the thickness of germinal epithelium, arrest of spermatogenesis at spermatid stage (late maturation arrest) and reduction in the number of Leydig cells. Gene expression levels of two SSCs markers (GFRα1 and CSF1) responsible for self-renewal were relatively counter-balanced. In conclusion, T. officinale whole plant and leaves aqueous extracts changed the gene expression of two SSCs markers leading to the imbalance between spermatogonia self-renewal and differentiation causing late maturation arrest.