Synthesis and Biological Evaluation of Xanthone Derivatives as Anti-Cancer Agents Targeting Topoisomerase II and DNA

Topoisomerase is one of the most important targets of anticancer drugs. In order to develop effective and low-toxic topoisomerase inhibitors, a series of xanthone derivatives have been designed and synthesized using the principles of skeleton transition. In vitro growth inhibition experiments of human breast cancer(MCF-7), gastric cancer (MGC-803), and cervical cancer(Hela) cell lines were used to evaluate the compound's anti-tumor cell proliferation activity. Most of the compounds showed anti-tumor growth activity, and also showed low toxicity to human normal cells L929. In the enzyme activity inhibition experiment, compounds 7d and 8d showed the best inhibitory activity. The DNA binding studies disclosed that the most potent compounds 7d and 8d can intercalate into DNA, induce apoptosis in MGC-803 cells and arrested at G2/M phase. Molecular docking showed that compounds 7d and 8d could bind with topoisomerase II and DNA through hydrogen bonds and π-stacking interactions.

Study of an Environmentally Friendly Method for the Dissolution of Precious Metal with Ionic Liquid and Iodoalkane

Gold as a precious metal resource has high recycling significance. However, the current extraction methods cannot achieve the both efficiency and environmental friendliness. In this paper, we propose a new gold leaching agent, which can leach gold under light condition by mixing iodoform (CHI3) with 1-butyl-3-methylimidazolium dicyanamide (BmimN(CN)2) ionic liquid. Under 25 °C and 13 W incandescent lamp irradiation, the leaching yield of gold can achieve 100 wt%, and the average leaching rate is 945 mg Au/(h·mol·CHI3) (18.9 times of that of the cyanidation method). Through the analysis of the results of radical inhibition experiment, UV-Vis and XPS, a possible leaching mechanism is proposed: the iodine radical generated by light oxidizes Au0 to Au+, and then forms AuN(CN)2 by coordinating with N(CN)2−. Subsequently, the ionic liquid and Au N(CN)2 form a stable [Bmim]·[Au(N(CN)2)2] ion pair structure, further promoting the dissolution reaction. The leaching yield of gold can reach 81.9 wt% and 100 wt%, respectively, when applied to ore and waste electrical and electronic equipment (WEEE); the leaching yield of gold can also reach 100 wt% when applied to a waste catalyst by adding a Soxhlet extraction. The results show that this method is not only efficient, mild, and environmentally friendly, but also has strong adaptability and wide application prospects.

Study of quality markers of antiuric acid formula by grey relational analysis

Gout has become a global problem, antiuric acid formula (AAF) is a clinical prescription highly effective in reducing uric acid levels. In order to find its quality control standards and contribute to the treatment of gout in the future, we adopted high-performance liquid chromatography and orbitrap liquid chromatography–mass spectrometry to establish fingerprints of 13 batches of AAF. The different batches of AAF were tested the activity of inhibit uric acid by the xanthine oxidase inhibition experiment. Grey relational analysis and bio-activity validation to assess the spectrum–effect relationship. Finally, we choose puerarin, calycosin-7-O-beta-d-glucoside and puerarin apioside as the AAF quality control component, and its average content is 6036.006 μg/g, 296.113 μg/g and 878.285 μg/g. As the quality control components of AAF, puerarin, calycosin-7-O-beta-d-glucoside and puerarin apioside can be of great significance for the treatment of gout and gout related research.

Targeted micelles with chemotherapeutics and gene drugs to inhibit the G1/S and G2/M mitotic cycle of prostate cancer

Background Chemotherapy and gene therapy are used in clinical practice for the treatment of castration-resistant prostate cancer. However, the poor efficiency of drug delivery and serious systemic side effects remain an obstacle to wider application of these drugs. Herein, we report newly designed PEO-PCL micelles that were self-assembled and modified by spermine ligand, DCL ligand and TAT peptide to carry docetaxel and anti-nucleostemin siRNA. Results The particle size of the micelles was 42 nm, the zeta potential increased from − 12.8 to 15 mV after grafting with spermine, and the optimal N/P ratio was 25:1. Cellular MTT experiments suggested that introduction of the DCL ligand resulted in high toxicity toward PSMA-positive cells and that the TAT peptide enhanced the effect. The expression of nucleostemin was significantly suppressed in vitro and in vivo, and the tumour-inhibition experiment showed that the dual-drug delivery system suppressed CRPC tumour proliferation. Conclusions This targeted drug delivery system inhibited the G1/S and G2/M mitotic cycle via synergistic interaction of chemotherapeutics and gene drugs.

Regulation Efficacy and Mechanism of the Toxicity of Microcystin-LR Targeting Protein Phosphatase 1 via the Biodegradation Pathway

Biodegradation is important to regulate the toxicity and environmental risk of microcystins (MCs). To explore their regulation effectiveness and mechanism, typical biodegradation products originating from microcystin-LR (MCLR) were prepared and purified. The protein phosphatase 1 (PP1) inhibition experiment showed the biodegradation pathway was effective in regulating the toxicity of the biodegradation products by extending the biodegradation. With the assistance of molecular docking, the specific interaction between the toxins and PP1 was explored. The MCLR/MCLR biodegradation products combined with PP1 mainly by the aid of interactions related to the active sites Adda5, Glu6, Mdha7, and the ionic bonds/hydrogen bonds between the integral toxin and PP1. As a consequence, the interactions between Mn22+ and Asp64/Asp92 in the catalytic center were inhibited to varying degrees, resulting in the reduced toxicity of the biodegradation products. During the biodegradation process, the relevant key interactions might be weakened or even disappear, and thus the toxicity was regulated. It is worth noting that the secondary pollution of the partial products (especially for Adda5-Glu6-Mdha7-Ala1 and the linearized MCLR), which still possessed the major active sites, is of deep concern.

The 3 × 120° rotary mechanism ofParacoccus denitrificansF1-ATPase is different from that of the bacterial and mitochondrial F1-ATPases

The rotation ofParacoccus denitrificansF1-ATPase (PdF1) was studied using single-molecule microscopy. At all concentrations of adenosine triphosphate (ATP) or a slowly hydrolyzable ATP analog (ATPγS), above or belowKm, PdF1showed three dwells per turn, each separated by 120°. Analysis of dwell time between steps showed that PdF1executes binding, hydrolysis, and probably product release at the same dwell. The comparison of ATP binding and catalytic pauses in single PdF1molecules suggested that PdF1executes both elementary events at the same rotary position. This point was confirmed in an inhibition experiment with a nonhydrolyzable ATP analog (AMP-PNP). Rotation assays in the presence of adenosine diphosphate (ADP) or inorganic phosphate at physiological concentrations did not reveal any obvious substeps. Although the possibility of the existence of substeps remains, all of the datasets show that PdF1is principally a three-stepping motor similar to bacterial vacuolar (V1)-ATPase fromThermus thermophilus. This contrasts with all other known F1-ATPases that show six or nine dwells per turn, conducting ATP binding and hydrolysis at different dwells. Pauses by persistent Mg-ADP inhibition or the inhibitory ζ-subunit were also found at the same angular position of the rotation dwell, supporting the simplified chemomechanical scheme of PdF1. Comprehensive analysis of rotary catalysis of F1from different species, including PdF1, suggests a clear trend in the correlation between the numbers of rotary steps of F1and Fodomains of F-ATP synthase. F1motors with more distinctive steps are coupled with proton-conducting Forings with fewer proteolipid subunits, giving insight into the design principle the F1Foof ATP synthase.

Green corrosion inhibition of mild steel using Prunus Dulcis seeds extract in an acidic medium

Synthetic inhibitors use by industries often have adverse effect on the environment. This work therefore investigates the use of plant extract as an inhibition to mild steel corrosion in an acidic environment. Weight loss method was adopted to evaluate inhibition efficiency by plant extract as corrosion inhibitors. Almond seeds (Prunusdulcis) was extracted with the aid of Soxhlet apparatus. The corrosion inhibition experiment was performed by setting up reactors containing mild steel coupon with variable concentrations of plant extract and 200ml of 1.5M HCl solution. The study revealed that the extract was an efficient inhibitor and was most effective as the concentration increased from 0.81% at 0.01g/ml to 69.95% at 0.15g/ml respectively. Adsorption study on mild steel surface showed that the experimental data fitted better into the Temkin isotherm with regression R2 closer to unity. Arrhenius constant and activation energy estimated at temperatures 308K to 328K revealed that activation energy aE increased with increasing inhibitor concentration from 5348.23J/mol at 0.01g/ml to 6151.44J/mol at 0.05g/ml. The outcome of the study revealed that mild steel is susceptible to corrosionwhich is capable of destroying the material and increasing inhibitor concentration and temperature has significant influence on the corrosion. Keywords: Mild steel, Corrosion, Inhibitor, Plant Extract, Adsorption

Radiosynthesis, in vitro and preliminary in vivo evaluation of the novel glutamine derived PET tracers [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine

IntroductionGlucose has been deemed the driving force of tumor growth for decades. However, research has shown that several tumors metabolically shift towards glutaminolysis. The development of radiolabeled glutamine derivatives could be a useful molecular imaging tool for visualizing these tumors. We elaborated on the glutamine-derived PET tracers by developing two novel probes, namely [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamineMaterials and methodsBoth tracers were labelled with fluorine-18 using our recently reported ruthenium-based direct aromatic fluorination method. Their affinity was evaluated with a [3H]glutamine inhibition experiment in a human PC-3 and a rat F98 cell line. The imaging potential of [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine was tested using a mouse PC-3 and a rat F98 tumor model.ResultsThe radiosynthesis of both tracers was successful with overall non-decay corrected yields of 18.46 ± 4.18 % (n=10) ([18F]fluorophenylglutamine) and 8.05 ± 3.25 % (n=5) ([18F]fluorobiphenylglutamine). In vitro inhibition experiments showed a moderate and low affinity of fluorophenylglutamine and fluorobiphenylglutamine, respectively, towards the human ASCT-2 transporter. Both compounds had a low affinity towards the rat ASCT-2 transporter. These results were endorsed by the in vivo experiments with low uptake of both tracers in the F98 rat xenograft, low uptake of [18F]FBPG in the mice PC-3 xenograft and a moderate uptake of [18F]FPG in the PC-3 tumors.ConclusionWe investigated the imaging potential of two novel PET radiotracers [18F]FPG and [18F]FBPG. [18F]FPG is the first example of a glutamine radiotracer derivatized with a phenyl group which enables the exploration of further derivatization of the phenyl group to increase the affinity and imaging qualities. We hypothesize that increasing the affinity of [18F]FPG by optimizing the substituents of the arene ring can result in a high-quality glutamine-based PET radiotracer.Advances in Knowledge and Implications for patient careWe hereby report novel glutamine-based PET-tracers. These tracers are tagged on the arene group with fluorine-18, hereby preventing in vivo defluorination, which can occur with alkyl labelled tracers (e.g. (2S,4R)4-[18F]fluoroglutamine). [18F]FPG shows clear tumor uptake in vivo, has no in vivo defluorination and has a straightforward production. We believe this tracer is a good starting point for the development of a high-quality tracer which is useful for the clinical visualization of the glutamine transport.

The clinical characteristics and molecular mechanism of pituitary adenoma associated with meningioma

Background Pituitary adenoma and meningioma are the most common benign tumors in the central nervous system. Pituitary adenoma associated with meningioma (PAM) is a rare disease and the clinical features and mechanisms of PAM are unclear. Methods We summarized the clinical data of 57 PAM patients and compared with sporadic pituitary adenoma (SPA) and sporadic meningioma (SM). 5 pituitary adenomas of PAM and 5 SPAs were performed ceRNA microarray. qRT-PCR, Western Blot, siMEN1 and rapamycin inhibition experiment were validated for ceRNA microarray. Results Clinical variable analyses revealed that significant correlations between PAM and female sex as well as older age when compared with SPA and significant correlations between PAM and transitional meningioma as well as older age when compared with SM. Additionally, the characteristics of PAM were significantly different for MEN1 patients. Functional experiments showed lower expression of MEN1 can upregulate mTOR signaling, in accordance with the result of ceRNA microarray. Rapamycin treatment promotes apoptosis in primary pituitary adenoma and meningioma cells of PAM. Conclusions MEN1 plays an important role in PAM by upregulating mTOR signaling pathway. Rapamycin represents a potential therapeutic strategy for PAM in the future.

Rutacecarpine Inhibits Angiogenesis by Targeting the VEGFR2 and VEGFR2-Mediated Akt/mTOR/p70s6k Signaling Pathway

This study aimed to investigate the effect of Ru (Rut) on angiogenesis, and the underlying regulation mechanism of signal transduction. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, adhesion inhibition experiment, migration inhibition experiment, and chick embryo chorioallantoic membrane (CAM) assays were performed on models of angiogenesis. The potential targets of rutaecarpine (Ru) were reverse screened with Discovery Studio 2017. The interaction between the compound and target were detected by surface plasmon resonance (SPR), enzyme-activity experiment, and Western blot assay. The obtained results confirmed that Ru exhibited modest inhibitory activity against human umbilical vein endothelial cells (HUVECs) (IC50 =16.54 ± 2.4 μM) and remarkable inhibitive effect against the migration and adhesion of HUVECs, as well as significant anti-angiogenesis activities in the CAM assay. The possible targets of vascular endothelial growth factor receptor 2 (VEGFR2) were identified by computer-aided simulation. Results showed a good binding relationship between the ligand and target through molecular docking, and this relationship was confirmed by SPR analysis. Furthermore, enzyme-activity experiment and western blot assay showed that Ru remarkably inhibited the activity of VEGFR2 and blocked the VEGFR2-mediated Akt/ (mTOR)/p70s6k signaling pathway in vitro. Ru can be a potential drug candidate for cancer prevention and cancer therapy.