Movement of TNT and RDX from composition B detonation residues in solution and sediment during runoff.

Energetics used in military exercises can potentially contaminate ground and surface waters. This study was conducted to evaluate the movement of Composition B, a formulation that includes TNT (2,4,6-trinitrotoluene), RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine), and HMX (octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine), in runoff. Mechanisms of transport we examined include movement of energetics dissolved in runoff, as particles and adsorbed to suspended sediment, and in infiltration. Rainfall simulations were conducted under controlled conditions with two rainfall rates (approximately 30 and 50 mm h-1), two soils with different infiltration capacities, and four energetic particle sizes (4.75-9.51 mm, 2.83-4.75 mm, 2-2.83 mm, and <2 mm). Particles remaining on the soil surface after rainfall were measured as well as energetics dissolved in runoff, in suspended sediment, and in infiltration. Greater concentrations of TNT than RDX and HMX were found dissolved in runoff due to its higher solubility and dissolution rates. We also found that particle transport in runoff increased with decrease in particle size. Smaller particle sizes also led to greater transport dissolved in solution. Relationships were found relating runoff and sediment yield to the transport of RDX and TNT. The results of this study allow improved prediction of Composition B transport in runoff and therefore its contamination potential.

[Research progress on chemical structures and pharmacological effects of natural cytisine and its derivatives].

Cytisine derivatives are a group of alkaloids containing the structural core of cytisine, which are mainly distributed in Fabaceae plants with a wide range of pharmacological activities, such as resisting inflammation, tumors, and viruses, and affecting the central nervous system. At present, a total of 193 natural cytisine and its derivatives have been reported, all of which are derived from L-lysine. In this study, natural cytisine derivatives were classified into eight types, namely cytisine type, sparteine type, albine type, angustifoline type, camoensidine type, cytisine-like type, tsukushinamine type, and lupanacosmine type. This study reviewed the research progress on the structures, plant sources, biosynthesis, and pharmacological activities of alkaloids of various types.

Variations of microbiota in three types of typical military contaminated sites: Diversities, structures, influence factors, and co-occurrence patterns.

Contamination with energetic compounds (ECs) is common in military sites and poses a great risk to the environment and human health. However, its effects on the soil bacterial communities remain unclear. This study assessed the variations of bacterial communities, co-occurrence patterns, and their influence factors in three types of typical military-contaminated sites (artillery range, military-industrial site, and ammunition destruction site). The results showed that the most polluted sites were ammunition destruction sites, followed by military-industrial sites, whereas pollution in the artillery ranges was minimal. The average concentrations of ECs including 2,4,6-trinitrotoluene (TNT), hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) in the study sites ranged 120-1.67 × 105, 20-7.20 × 104, and 180-2.38 × 105 µg/kg, respectively. Bacterial diversity and community structure in military-industrial and ammunition destruction sites were significantly changed, but not in artillery ranges. TNT, pH, and soil moisture are the critical factors affecting bacterial communities in contaminated military sites. Co-occurrence network analysis indicated that the pressure of ECs affected bacterial interactions and microbiota function. Our findings provide new insights into the variations in bacterial communities in EC-contaminated military sites and references for the bioremediation of ECs.

Research progress on chemical structures and pharmacological effects of natural cytisine and its derivatives / 中国中药杂志

Cytisine derivatives are a group of alkaloids containing the structural core of cytisine, which are mainly distributed in Fabaceae plants with a wide range of pharmacological activities, such as resisting inflammation, tumors, and viruses, and affecting the central nervous system. At present, a total of 193 natural cytisine and its derivatives have been reported, all of which are derived from L-lysine. In this study, natural cytisine derivatives were classified into eight types, namely cytisine type, sparteine type, albine type, angustifoline type, camoensidine type, cytisine-like type, tsukushinamine type, and lupanacosmine type. This study reviewed the research progress on the structures, plant sources, biosynthesis, and pharmacological activities of alkaloids of various types.

Uncovering the structure and function of specialist bacterial lineages in environments routinely exposed to explosives.

Environmental contamination by hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), the two most widely used compounds for military operations, is a long-standing problem at the manufacturing and decommissioning plants. Since explosives contamination has previously been shown to favour the growth of specific bacterial communities, the present study attempts to identify the specialist bacterial communities and their potential functional and metabolic roles by using amplicon targeted and whole-metagenome sequencing approaches in samples collected from two distinct explosives manufacturing sites. We hypothesize that the community structure and functional attributes of bacterial population are substantially altered by the concentration of explosives and physicochemical conditions. The results highlight the predominance of Planctomycetes in contrast to previous reports from similar habitats. The detailed phylogenetic analysis revealed the presence of operational taxonomic units related to bacterial members known for their explosives degradation. Further, the functional and metabolic analyses highlighted the abundance of putative genes and unidentified taxa possibly associated with xenobiotic biodegradation. Our findings suggest that microbial species capable of utilizing explosives as a carbon, energy or electron source are favoured by certain selective pressures based on the prevailing physicochemical and geographical conditions.

Fluorescence activation mechanism and imaging of drug permeation with new sensors for smoking-cessation ligands.

Nicotinic partial agonists provide an accepted aid for smoking cessation and thus contribute to decreasing tobacco-related disease. Improved drugs constitute a continued area of study. However, there remains no reductionist method to examine the cellular and subcellular pharmacokinetic properties of these compounds in living cells. Here, we developed new intensity-based drug-sensing fluorescent reporters (iDrugSnFRs) for the nicotinic partial agonists dianicline, cytisine, and two cytisine derivatives - 10-fluorocytisine and 9-bromo-10-ethylcytisine. We report the first atomic-scale structures of liganded periplasmic binding protein-based biosensors, accelerating development of iDrugSnFRs and also explaining the activation mechanism. The nicotinic iDrugSnFRs detect their drug partners in solution, as well as at the plasma membrane (PM) and in the endoplasmic reticulum (ER) of cell lines and mouse hippocampal neurons. At the PM, the speed of solution changes limits the growth and decay rates of the fluorescence response in almost all cases. In contrast, we found that rates of membrane crossing differ among these nicotinic drugs by >30-fold. The new nicotinic iDrugSnFRs provide insight into the real-time pharmacokinetic properties of nicotinic agonists and provide a methodology whereby iDrugSnFRs can inform both pharmaceutical neuroscience and addiction neuroscience.

Isolation and biological activity of azocine and azocane alkaloids.

Thousands of known alkaloids contain a nitrogen (N) heterocycle. While five-, six- and seven-membered N-heterocycles (ie: pyrroles, imidazoles, indoles, pyridines and azepines and their saturated variants) are common, those with an eight-membered N-heterocycle are comparatively rare. This review discusses the structure and bioactivity of alkaloids that contain an azocine (or saturated azocane) ring, and the array of sources whence they originate.

Synthesis and antiviral evaluation of cytisine derivatives against dengue virus types 1 and 2.

Dengue virus (DENV) causes about 50-100 million cases per year worldwide. However, there is still a big challenge in developing antiviral drugs against DENV infection. Some derivatives of alkaloid (-)-cytisine, like other alkaloid analogs, have been proposed for their antiviral potential. This study investigated antiviral activity and mechanisms of the cytisine derivatives, and discovered the structure-activity relationship against DENV. The antiviral assays were performed using one strain of DENV1 and DENV2, and two cell lines Vero E6 and A549. The structure-activity relationship of the effective compounds was also evaluated using combination of time-of-addition/removal assay and molecular docking. Compounds 3, 4, 12 (N-allylcytisine-3-thiocarbamide), 16, and 20 exhibited the high antiviral activity with IC50 values of lower than 3 µM against DENV1 and DENV2. Of them, the derivative 12 showed the highest antiviral activities against DENV1 (IC50 = 0.14 µM) and DENV-2 (IC50 = <0.1 µM), exhibiting the potent inhibition on virus attachment and entry stages. Meanwhile, the compounds 4 and 20 had a strong inhibition at the post-entry stage (IC50 = <0.1 µM). A correlation between the experimental pIC50 values and predicted pKi calculated by docking of compounds into DENV E protein was significant, correlating with the impact of compound 12 on the attachment stage, but compounds 4, and 20 on post-entry stage. The results provided the insight into the directions of synthetic modifications of starting (-)-cytisine as the inhibitors of DENV E protein at attachment and entry stages of DENV life cycle.

Insecticidal activity of twin compounds from podophyllotoxin and cytisine.

To explore natural-product-based insecticide candidates, and high value-added application of natural plants in agriculture, a series of twin compounds were prepared from two natural products podophyllotoxin and cytisine, which are isolated from the plants Podophyllum hexandrum and Thermopsis lanceolata, respectively. Compounds IIa (X = Cl, Y = R1 = R2 = H), IIIc (X = Y = R1 = R2 = Cl) and IVd (X = R1 = R2 = Br, Y = H) exhibited >2-fold potent insecticidal activity of podophyllotoxin against armyworm with FMRs greater than 60%. SARs were also observed. It is noteworthy that the idea of twin insecticides was addressed for the first time. We hope this idea will be conducive to design new twin insecticidal agents, and lay the foundation for future high value-added application of the plants P. hexandrum and T. lanceolata as potentially botanical pesticides in agriculture.

1,3-Oxazole derivatives of cytisine as potential inhibitors of glutathione reductase of Candida spp.: QSAR modeling, docking analysis and experimental study of new anti-Candida agents.

Natural products as well as their derivatives play a significant role in the discovery of new biologically active compounds in the different areas of our life especially in the field of medicine. The synthesis of compounds produced from natural products including cytisine is one approach for the wider use of natural substances in the development of new drugs. QSAR modeling was used to predict and select of biologically active cytisine-containing 1,3-oxazoles. The eleven most promising compounds were identified, synthesized and tested. The activity of the synthesized compounds was evaluated using the disc diffusion method against C. albicans M 885 (ATCC 10,231) strain and clinical fluconazole-resistant Candida krusei strain. Molecular docking of the most active compounds as potential inhibitors of the Candida spp. glutathione reductase was performed using the AutoDock Vina. The built classification models demonstrated good stability, robustness and predictive power. The eleven cytisine-containing 1,3-oxazoles were synthesized and their activity against Candida spp. was evaluated. Compounds 10, 11 as potential inhibitors of the Candida spp. glutathione reductase demonstrated the high activity against C. albicans M 885 (ATCC 10,231) strain and clinical fluconazole-resistant Candida krusei strain. The studied compounds 10, 11 present the interesting scaffold for further investigation as potential inhibitors of the Candida spp. glutathione reductase with the promising antifungal properties. The developed models are publicly available online at http://ochem.eu/article/120720 and could be used by scientists for design of new more effective drugs.

Cancer cell death using metabolic glycan labelling techniques.

Herein we describe a method for inducing cancer cell death, which relies on the use of a H2O2-responsive glycan metabolic precursor in conjunction with antibody-dependent cellular cytotoxicity (ADCC) or photodynamic therapy (PDT).

CL-20-Based Cocrystal Energetic Materials: Simulation, Preparation and Performance.

The cocrystallization of high-energy explosives has attracted great interests since it can alleviate to a certain extent the power-safety contradiction. 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaaza-isowurtzitane (CL-20), one of the most powerful explosives, has attracted much attention for researchers worldwide. However, the disadvantage of CL-20 has increased sensitivity to mechanical stimuli and cocrystallization of CL-20 with other compounds may provide a way to decrease its sensitivity. The intermolecular interaction of five types of CL-20-based cocrystal (CL-20/TNT, CL-20/HMX, CL-20/FOX-7, CL-20/TKX-50 and CL-20/DNB) by using molecular dynamic simulation was reviewed. The preparation methods and thermal decomposition properties of CL-20-based cocrystal are emphatically analyzed. Special emphasis is focused on the improved mechanical performances of CL-20-based cocrystal, which are compared with those of CL-20. The existing problems and challenges for the future work on CL-20-based cocrystal are discussed.

Pharmacokinetics, Tissue Distribution, and Druggability Prediction of the Natural Anticancer Active Compound Cytisine N-Isoflavones Combined with Computer Simulation.

Cytisine N-methylene-(5,7-dihydroxy-4'-methoxy)-isoflavone (CNF2) is a new compound isolated from the Chinese herbal medicine Sophora alopecuroides. Preliminary pharmacodynamic studies demonstrated its activity in inhibiting breast cancer cell metastasis. This study examined the pharmacokinetics, absolute bioavailability, and tissue distribution of CNF2 in rats, and combined computer-aided technology to predict the druggability of CNF2. The binding site of CNF2 and the breast cancer target human epidermal growth factor receptor-2 (HER2) were examined with molecular docking technology. Next, ACD/Percepta software was used to predict the druggability of CNF2 based on the quantitative structure-activity relationship (QSAR). Finally, a simple and effective HPLC method was used to determine plasma pharmacokinetics and tissue distribution of CNF2 in rats. Prediction and experimental results show that compared with the positive control HER2 inhibitor SYR127063, CNF2 has a stronger binding affinity with HER2, suggesting that its efficacy is stronger; and the structure of CNF2 complies with the Lipinski's Rule of Five and has good drug-likeness. The residence time of CNF2 in rats is less than 4 h, and the metabolic rate is relatively fast; But the absolute bioavailability of CNF2 in rats was 6.6%, mainly distributed in the stomach, intestine, and lung tissues, where the CNF2 contents were 401.20, 144.01, and 245.82 µg/g, respectively. This study constructed rapid screening and preliminary evaluation of active compounds, which provided important references for the development and further research of such compounds.

The thermodynamic profile and molecular interactions of a C(9)-cytisine derivative-binding acetylcholine-binding protein from Aplysia californica.

Cytisine, a natural product with high affinity for clinically relevant nicotinic acetylcholine receptors (nAChRs), is used as a smoking-cessation agent. The compound displays an excellent clinical profile and hence there is an interest in derivatives that may be further improved or find use in the treatment of other conditions. Here, the binding of a cytisine derivative modified by the addition of a 3-(hydroxypropyl) moiety (ligand 4) to Aplysia californica acetylcholine-binding protein (AcAChBP), a surrogate for nAChR orthosteric binding sites, was investigated. Isothermal titration calorimetry revealed that the favorable binding of cytisine and its derivative to AcAChBP is driven by the enthalpic contribution, which dominates an unfavorable entropic component. Although ligand 4 had a less unfavorable entropic contribution compared with cytisine, the affinity for AcAChBP was significantly diminished owing to the magnitude of the reduction in the enthalpic component. The high-resolution crystal structure of the AcAChBP-4 complex indicated close similarities in the protein-ligand interactions involving the parts of 4 common to cytisine. The point of difference, the 3-(hydroxypropyl) substituent, appears to influence the conformation of the Met133 side chain and helps to form an ordered solvent structure at the edge of the orthosteric binding site.

A novel hybrid method named electron conformational genetic algorithm as a 4D QSAR investigation to calculate the biological activity of the tetrahydrodibenzazosines.

To understand the structure-activity correlation of a group of tetrahydrodibenzazocines as inhibitors of 17ß-hydroxysteroid dehydrogenase type 3, we have performed a combined genetic algorithm (GA) and four-dimensional quantitative structure-activity relationship (4D-QSAR) modeling study. The computed electronic and geometry structure descriptors were regulated as a matrix and named as electron-conformational matrix of contiguity (ECMC). A chemical property-based pharmacophore model was developed for series of tetrahydrodibenzazocines by EMRE software package. GA was employed to choose an optimal combination of parameters. A model has been developed for estimating anticancer activity quantitatively. All QSAR models were established with 40 compounds (training set), then they were considered for selective capability with additional nine compounds (test set). A statistically valid 4D-QSAR ( Rtraining2=0.856 , Rtest2=0.851 and q2 = 0.650) with good external set prediction was obtained.

Unsymmetrically Substituted Dibenzo[b,f][1,5]-diazocine-6,12(5H,11H)dione-A Convenient Scaffold for Bioactive Molecule Design.

A novel approach for the synthesis of unsymmetrically substituted dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones has been developed. This facile three-step method uses variously substituted 1H-benzo[d][1,3]oxazine-2,4-diones (isatoic anhydrides) and 2-aminobenzoic acids as a starting materials. The obtained products were further transformed into N-alkyl-, N-acetyl- and dithio analogues. Developed procedures allowed the synthesis of unsymmetrical dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones and three novel heterocyclic scaffolds: benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)dione, pyrido[3,2-c][1,5]benzodiazocine-5,11(6H,12H)-dione and pyrazino[3,2-c][1,5]benzodiazocine-6,12(5H,11H)dione. For 11 of the compounds crystal structures were obtained. The preliminary cytotoxic effect against two cancer (HeLa, U87) and two normal lines (HEK293, EUFA30) as well as antibacterial activity were determined. The obtained dibenzo[b,f][1,5]diazocine(5H,11H)6,12-dione framework could serve as a privileged structure for the drug design and development.

Characterization of Crystal Microstructure Based on Small Angle X-ray Scattering (SAXS) Technique.

Small-angle X-ray scattering (SAXS) is an effective method to obtain microstructural information of materials. However, due to the influence of crystal surface effects, SAXS has a deviation in the characterization of the crystal microstructure. In order to solve the influence of crystal surface effect on the internal defect signal, the microstructure of Octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) crystal was characterized by soaking the sample in the matching solution. We found that the absolute scattering intensity, specific surface and volume fraction of the sample in the matching solution are significantly lower than the initial sample, which solves the influence of the crystal surface effect on the test results. Comparing the scattering results of the samples in different electron density matching solutions, it was found that the best result was obtained when using GPL-107 perfluoropolyether (PFPE) matching solution and the same law was obtained by controlling the experiment with 2,4,6,8,10,12-hexanitrohexaazaisowurtzitane (CL-20) crystal. The fitting density was calculated according to the theoretical density and void volume fraction of the sample, and the calculated results are close to the test results of Particle Density Distribution Analyzer (PDDA). Based on this paper, we provide a method to obtain the correct information of crystal microstructure.

Stereodirected synthesis of alkaloid-like quinolizidine systems.

New stereoselective methods for the chemical modification of cytisine based on T-reactions are reported. A reaction of cytisine with 2-chloro-5-nitrobenzaldehyde and followed condensation with 1,3-dimethylbarbituric acid affords N-(5-nitro-2-{1,3-dimethylperhydropyrimidine-2,4,6-trione-5-methynyl})cytisine, which undergoes a cyclization with the tetrahydropyridine ring closure. The cyclization proceeds via two competing routes yielding 5,5-spirobarbituric acid derivatives with 11,19-diaza-pentacyclo[11.7.1.02,11.05,10.014,19]henicosane and 11,15-diazapentacyclo-[11.7.1.02,11.05,10.015,20]henicosane skeletons. The cyclization reaction in solutions afford either 24.25-trans and 15,16-trans isomers or trans and cis isomer mixtures, depending on the specific solvent. Meanwhile, 24,25-cis and 15,16-cis isomers are formed stereoselectively under heterogeneous conditions in water suspensions. Trans-5,5-spirobarbiturates under similar conditions undergo isomerization into more stable cis-analogs by the configuration inversion at the C7 atom. The synthesized 5,5-spirobarbituric acid derivatives were successfully converted into alkaloid-like quinolizidine systems (1R,2R,3R,13S)-7-nitro-18-oxo-11,19-diazapentacyclo[11.7.1.02,11.05,10.014,19]henicosa-5(10),6,8,14,16-pentaene-3-carboxylic acid and (1R,2S,3S,13S)-nitro-16-oxo-11,15-diazapentacyclo[11,7,1.02,11,05,10,015,20]henicosa-5,7,9,17,19-pentaene-3-carboxylic acid and their derivatives via the spiropyrimidine moiety removal by the stereoselective hydrolysis. The molecular and crystal structures of the target substances were elucidated by X-ray crystallography and NMR.

A turn-off fluorescence probe based on terpyridine for pH monitoring.

A new pH-dependent fluorescence probe 2,8-bis((E)-4-([2,2':6',2″-terpyridin]-4'-yl)styryl)-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (TBPTP) based on Tröger's base (TB) bound to terpyridine was designed and synthesized. Photophysical properties and titration experiments of TBPTP were investigated by absorption and fluorescence spectroscopy. TBPTP exhibited high sensitivity in an acidic environment with the working pH range 7.2-2.5, especially having a good liner response to pH changes in the range 2.5-4.3, which suggested that TBPTP is a good candidate for pH monitoring.

Advances on the Bioactivities, Total Synthesis, Structural Modification, and Structure-Activity Relationships of Cytisine Derivatives.

Cytisine is a quinolizidine alkaloid isolated from various Leguminosae plants. Cytisine and its derivatives exhibit a broad range of biological properties, such as smoking cessation aid, antidepressant, neuroprotective, nootropic, anticancer, antiviral, antiparasitic, antidiabetic, insecticidal, and nematicidal activities. In this review, the progress of cytisine and its derivatives in regard to bioactivities, total synthesis, structural modifications focusing on their N-12 position and lactam ring is reported. Additionally, the structure-activity relationships of cytisine and its derivatives are also discussed.