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Purpose Methotrexate is one of the widely used agents to treat various solid tumors, although its usage brings some challenges because of its poor bioavailability and/or dose-dependent side efects. Increasing the solubility, permeability, and consequently bioavailability in company with minimizing side efects are always desired to formulate such these drugs. In this paper, we concentrated on formulation parameters of methotrexate-loaded niosomes, in an attempt to facilitate its solubility. Methods Various formulation parameters were utilized, including surfactant types, the amount of membrane additives, and types of hydrating agent. Methotrexate-loaded niosomes were fully characterized. The cell viability and hemolysis assay were evaluated. The efects of developed formulation on cellular interaction, growing, and micronuclei assay were also investigated. Results Methotrexate (MTX)-loaded niosomes were produced in small particle size (241.3±65.7 nm) with high uniformity using sodium hydroxide as hydrating solution. Their entrapment efciency was 59.5±3.0% and the release completed in 6 h. The incorporation of methotrexate into niosomes was confrmed, and their higher efciency on cell viability was presented. MTX-loaded niosomes were found safe and acceptable for parenteral administration. The number of apoptotic and dead cells were increased signifcantly in all types of cells treated with niosomes. The apoptosis-mediated cell death was triggered by produced niosomes. Conclusion This study suggests that MTX-loaded niosomes formulated with sodium hydroxide provided a signifcant improvement in niosome characteristics with the help of solubility enhancement strategies. The cellular assessments proved its potential efcacy. It is concluded that these promising results should be promoted in further studies.

Stearic acid (SA) and oleic acid (OA) which are inherently existing fatty acids (FAs) in the body can alter cell membrane function and interact with each other. However, discrepancies arise as to whether these effects are beneficial or harmful on the body. To resolve this ambiguity, there is a dire need to study how FAs can affect the etiology of diseases and their treatment. In this study, we aimed to investigate long chain FAs aggregation behaviors and their effects on membrane integrity and cell viability. We determined the critical aggregation concentration (CAC) of SA and OA (1110 mu M and 300 mu M, respectively which were less amount than that used in nanocarriers). In TEM images, hexagonal overlapped or fused structures of SA were seen, whereas quite small spherical clusters of OA were obtained. Membrane integrity assessments demonstrated that SA and OA at their own CAC and below could crack the lipid junctions on membrane mimicking systems. Moreover, they completely disrupt the membrane integrity above the CAC at pH 7.2. Cell viabilities on various cell lines were assessed after exposed to SA or OA aggregates. SA was more aggressive than OA on cell death in all cell lines. The effect of SA on PC3 cell lines was in a concentration-dependent manner. The effect of SA above CAC boosted the inhibition of cell viability. Furthermore, OA showed a proliferation effect on PC3 cells. Consequently, the aggregation behavior of FAs should be considered as a noteworthy factor in physiological functions.

A series of urolithin amide (i.e., URO-4-URO-10 and THU-4-THU-10) derivatives was designed and synthesized, and their chemical structures were confirmed with spectroscopic techniques and elemental analysis. The title compounds and synthesis intermediates (THU-1-THU-10 and URO-1-URO-10) were evaluated for their potential to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidase B (MAO-B). Compounds THU-4 and THU-8 were found to be the most potent inhibitors for the cholinesterases and MAO-B, respectively. The docking studies were also employed to evaluate the binding modes of the most active compounds with AChE, BuChE, and MAO-B. Furthermore, the moderate-to-strong activities of the compounds were also displayed in amyloid-beta inhibition and antioxidant assay systems. The results pointed out that the urolithin scaffold can be employed in drug design studies for the development of multitarget ligands acting on various cascades shown to be important within the pathophysiology of Alzheimer's disease.

WOS: 000460607700003, Background: The main factor for the prolongation of the ulcer treatment in the gastrointestinal system would be Helicobacter pylori infection, which can possibly lead to gastrointestinal cancer. Triple therapy is the treatment of choice by today's standards. However, observed resistance among the bacterial strains can make the situation even worse. Therefore, there is a need to discover new targeted antibacterial therapy in order to make success in the eradication of H. pylori infections. Methods: The targeted therapy rule is to identify the related macromolecules that are responsible for the survival of the bacteria. Thus, 2-[(2',4'-difluoro-4-hydroxybiphenyl-3-yl)carbonyl]-N-( substituted)hydrazinocarbothioamide (3-13) and 5-(2',4'-difluoro-4-hydroxybiphenyl-3-yl)-4-( substituted)-2,4-dihydro-3H-1,2,4-triazole-3-thiones (14-17) were synthesized and evaluated for antibacterial activity in vitro against H. pylori. Results: All of the tested compounds showed remarkable antibacterial activity compared to the standard drugs (Ornidazole, Metronidazole, Nitrimidazin and Clarithromycin). Compounds 4 and 13 showed activity as 2 mu g/ml MIC value. Conclusion: In addition, we have investigated binding modes and energy of the compounds 4 and 13 on urease enzyme active by using the molecular docking tools., Scientific and Technical Research Council of Turkey (TUBITAK) [114S966], This work was supported by The Scientific and Technical Research Council of Turkey (TUBITAK), Research Fund Project Number: 114S966. The authors are grateful to Dr. Jurgen Gross from the Institute of Organic Chemistry, University of Heidelberg, for his generous help in obtaining HR-EI/FAB mass spectra of the synthesized compounds. Diflunisal was supplied by Sanovel Pharmaceutical Industry Inc.

WOS: 000445295500134, PubMed ID: 30082676, Cyclooxygenase enzymes play a vital role in inflammatory pathways in the human body. Apart from their relation with inflammation, the additional involvement of COX-2 enzyme with cancer activity was recently discovered. In some cancer types the level of COX-2 enzyme is increased indicating that this enzyme could be a suitable target for cancer therapy. Based on these findings, we have synthesized some new diflunisal thiosemicarbazides and 1,2,4-triazoles and tested them against androgen-independent prostate adenocarcinoma (PC-3), colon carcinoma (HCT-116), human breast cancer (T47D), breast carcinoma (MCF7) and human embryonic kidney (HEK-293) cell lines. Specifically, the diflunisal and thiosemicarbazide functionality are combined during the synthesis of original compounds anticipating a potency enhancement. Compounds 6, 10, 15 and 16 did not show cytotoxic effects for the HEK293 cell line. Among them, compounds 15 and 16 demonstrated anticancer activity for the breast cancer cell line T47D, whereas compounds 6 and 10 which are thiosemicarbazide derivatives displayed anti-tumourigenic activity against the PC-3 cell line, consistent with the literature. However, no activity was observed for the HCT-116 cancer cell line with the tested thiosemicarbazide derivatives. Only compound 16 displayed activity against the HCT-116 cell line. Therefore, it was speculated that the diflunisal and thiosemicarbazide functionalities potentiate anticancer activity on prostate cancer and the thiosemicarbazide functionality decreases the anticancer activity of diflunisal on colon cancer cell lines. In order to gain insight into the anticancer activity and COX-2 inhibition, molecular docking studies were carried out for COX-1 and COX-2 enzymes utilizing the newly synthesized compounds 15, and 16. Both 15 and 16 showed high selectivity and affinity toward COX-2 isozyme over COX-1, which is in agreement with the experimental results., Scientific and Technical Research Council of Turkey (TUBITAK) [114S966]; Marie Sklodowska-Curie action, funding scheme: FP7-MC-ITN [608381], This work was supported by The Scientific and Technical Research Council of Turkey (TUBITAK), Research Fund Project Number: 114S966. The authors are grateful to Jurgen Gross from the Institute of Organic Chemistry, University of Heidelberg, for his generous help on obtaining HR-EI/FAB mass spectra of the synthesized compounds. Diflunisal was supplied by Sanovel Pharmaceutical Industry Inc, Istanbul, Turkey. Teodora Djikic kindly acknowledges "Training in Neurodegeneration, Therapeutics, Intervention and Neurorepair" project number 608381 funded by Marie Sklodowska-Curie action, funding scheme: FP7-MC-ITN.

A novel series of new tolmetin hydrazide derivatives, N -Alkyl/Arylsubstitued- 2-{[1-methyl-5-(4-methylbenzoyl)-1 H -pyrol-2-yl]acetyl}hydrazinecarbothioamides [ 4a-j ] have been synthesized in this study. The structures of the new compounds were determined by spectral (FT-IR, 1 H-NMR, 13 C-NMR and 2D-NMR) methods and their purity were proven by elemental analysis and TLC. Tolmetin [1] and N -(4-fluorophenyl) -2-{[1-methyl-5-(4-methylbenzoyl)-1 H- pyrol-2-yl]acetyl}hydrazinecarbothioamide [SGK-524; 4d] were evaluated for in vitro using the MTT colorimetric method for anticancer activity. Androjen-independed human prostate cancer cell line PC-3 (ATCC, CRL-1435) , human colon cancer cell lines HCT-116 (ATCC, CCL-247) and HT-29 (ATCC, HTB-38) were used in this study. Compound 4d exhibited anticancer activity against PC-3 whereas Tolmetin showed minor activity comparing to compound 4d .