New Organoselenium (NSAIDs-Selenourea and Isoselenocyanate) Derivatives as Potential Antiproliferative Agents: Synthesis, Biological Evaluation and in Silico Calculations.

In this study, we report on the synthesis of new organoselenium derivatives, including nonsteroidal anti-inflammatory drugs (NSAIDs) scaffolds and Se functionalities (isoselenocyanate and selenourea), which were evaluated against four types of cancer cell line: SW480 (human colon adenocarcinoma cells), HeLa (human cervical cancer cells), A549 (human lung carcinoma cells), MCF-7 (human breast adenocarcinoma cells). Among these compounds, most of the investigated compounds reduced the viability of different cancer cell lines. The most promising compound 6b showed IC50 values under 10 µM against the four cancer cell lines, particularly to HeLa and MCF-7, with IC50 values of 2.3 and 2.5 µM, respectively. Furthermore, two compounds, 6b and 6f, were selected to investigate their ability to induce apoptosis in MCF-7 cells via modulation of the expression of anti-apoptotic Bcl-2 protein, pro-inflammatory cytokines (IL-2) and proapoptotic caspase-3 protein. The redox properties of the NSAIDs-Se derivatives were conducted by 2, 2-didiphenyl-1-picrylhydrazyl (DPPH), bleomycin-dependent DNA damage and glutathione peroxidase (GPx)-like assays. Finally, a molecular docking study revealed that an interaction with the active site of thioredoxin reductase 1 (TrxR1) predicted the antiproliferative activity of the synthesized candidates. Overall, these results could serve as a promising launch point for further designs of NSAIDs-Se derivatives as potential antiproliferative agents.

Synthesis and Potential Anticancer Activity of Some Novel Selenocyanates and Diselenides.

In the present study, twenty-four selenocyanate and diselenide compounds were synthesized and characterized, and their anticancer activities against the human cancer cell lines Caco2, BGC-823, MCF-7 and PC-3 were determined. Interestingly, most of the new compounds were active in reducing the viability of different cancer cell lines. Two compounds exhibited higher promising activities than other derivatives. The most active compound showed the least IC50 values against the four cancer cell lines, particularly to PC-3 with IC50 values below 5 µm. Two compounds were selected to monitor the expression levels of Bcl-2, IL-2 and caspase-3 molecular biomarkers. Interestingly, the two compounds downregulated the Bcl-2 expression levels and upregulated the expression of IL-2 and caspase-3 in PC-3 cells compared to untreated cells. Moreover, most of the synthesized organoselenides exhibited good Gpx-like activities comparable to ebselen. These results appear that introduction of selenocyanate (-SeCN) or diselenides (-Se-Se-) moiety to some carboxy derivatives could serve as a promising launch point for the further design of this type of organic selenium anticancer agent.

Recent progresses in biomedical applications of aptamer-functionalized systems.

Aptamers, known as "chemical antibodies" are screened via a combinational technology of systematic evolution of ligands by exponential enrichment (SELEX). Due to their specific targeting ability, high binding affinity, low immunogenicity and easy modification, aptamer-functionalized systems have been extensively applied in various fields and exhibit favorable results. However, there is still a long way for them to be commercialized, and few aptamer-functionalized systems have yet successfully entered clinical and industrial use. Thus, it is necessary to overview the recent research progresses of aptamer-functionalized systems for the researchers to improve or design novel and better aptamer-functionalized systems. In this review, we first introduce the recent progresses of aptamer-functionalized systems' applications in biosensing, targeted drug delivery, gene therapy and cancer cell imaging, followed by a discussion of the challenges faced with extensive applications of aptamer-functionalized systems and speculation of the future prospects of them.

Tissue Distribution, Metabolism, and Excretion of 3,3'-Dichloro-4'-sulfooxy-biphenyl in the Rat.

Polychlorinated biphenyls (PCBs) with less chlorine atoms exhibit a greater susceptibility to metabolism than their more-chlorinated counterparts. Following initial hydroxylation of these less-chlorinated PCBs, metabolic sulfation to form PCB sulfates is increasingly recognized as an important component of their toxicology. Because procedures for the quantitative analysis of PCB sulfates in tissue samples have not been previously available, we have now developed an efficient, LC-ESI-MS/MS-based protocol for the quantitative analysis of 4-PCB 11 sulfate in biological samples. This procedure was used to determine the distribution of 4-PCB 11 sulfate in liver, kidney, lung, and brain as well as its excretion profile following its intravenous administration to male Sprague-Dawley rats. Following initial uptake of 4-PCB 11 sulfate, its concentration in these tissues and serum declined within the first hour following injection. Although biliary secretion was detected, analysis of 24 h collections of urine and feces revealed recovery of less than 4% of the administered 4-PCB 11 sulfate. High-resolution LC-MS analysis of bile, urine, and feces showed metabolic products derived from 4-PCB 11 sulfate. Thus, 4-PCB 11 sulfate at this dose was not directly excreted in the urine but was instead redistributed to tissues and/or subjected to further metabolism.

Aromatic organosulfates in atmospheric aerosols: synthesis, characterization, and abundance.

Aromatic organosulfates are identified and quantified in fine particulate matter (PM2.5) from Lahore, Pakistan, Godavari, Nepal, and Pasadena, California. To support detection and quantification, authentic standards of phenyl sulfate, benzyl sulfate, 3-and 4-methylphenyl sulfate and 2-, 3-, and 4-methylbenzyl sulfate were synthesized. Authentic standards and aerosol samples were analyzed by ultra-performance liquid chromatography (UPLC) coupled to negative electrospray ionization (ESI) quadrupole time-of-flight (ToF) mass spectrometry. Benzyl sulfate was present in all three locations at concentrations ranging from 4 - 90 pg m-3. Phenyl sulfate, methylphenyl sulfates and methylbenzyl sulfates were observed intermittently with abundances of 4 pg m-3, 2-31 pg m-3, 109 pg m-3, respectively. Characteristic fragment ions of aromatic organosulfates include the sulfite radical (•SO3-, m/z 80) and the sulfate radical (•SO4-,m/z 96). Instrumental response factors of phenyl and benzyl sulfates varied by a factor of 4.3, indicating that structurally-similar organosulfates may have significantly different instrumental responses and highlighting the need to develop authentic standards for absolute quantitation organosulfates. In an effort to better understand the sources of aromatic organosulfates to the atmosphere, chamber experiments with the precursor toluene were conducted under conditions that form biogenic organosulfates. Aromatic organosulfates were not detected in the chamber samples, suggesting that they form through different pathways, have different precursors (e.g. naphthalene or methylnaphthalene), or are emitted from primary sources.

Anti-cancer activity and mechanism of flurbiprofen organoselenium compound RY-1-92 in non-small cell lung cancer.

Lung cancer is one of the malignancies with the highest incidence and mortality rates worldwide, and non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer types. In this study, the anti-cancer activities of a novel flurbiprofen organic selenium compound, RY-1-92, on NSCLC cells and a mouse model and the underlying molecular mechanisms were explored. We found that compound RY-1-92 can significantly inhibit the viability, colony formation and migration of A549, NCI-H460 lung cancer cells. Flow cytometry analysis showed that RY-1-92 also can lead to G2/M cell cycle arrest and apoptosis induced in lung cancer cells. Further, RY-1-92 can decrease the tumor size in the Lewis lung cancer tumor-bearing mouse model. The protein levels of cell cycle-related proteins CDK1/cyclinB1 were decreased, while the apoptosis-related protein BAX was increased dramatically after RY-1-92 treatment in vitro and in vivo. Impressively, it was found that TRPV1 might act as a potential molecular target of RY-1-92 using the SEA search server. Furthermore, down-regulation on TRPV1 and its downstream associated factors including p-AKT protein and MAPK signaling pathway-related proteins after RY-1-92 treatment was observed in A549, NCI-H460 lung cancer cells. Taken together, our findings shed light on the potential of RY-1-92 as a novel small molecular drug for NSCLC, and it is of great significance for its further in-depth research and development.

3,4',5-Trichloro-biphenyl-4-yl 2,2,2-trichloro-ethyl sulfate.

Crystals of the title compound, C14H8Cl6O4S, are twinned by inversion, with unequal components [0.85 (3):0.15 (3)]. The asymmetric unit contains two independent mol-ecules that are related by a pseudo-inversion center. The Car-O [1.393 (9) and 1.397 (9) Å] and ester S-O bond lengths [1.600 (5) and 1.590 (5) Å] of both mol-ecules are comparable to the structurally related 2,3,5,5-trichloro-biphenyl-4-yl 2,2,2-trichloro-ethyl sulfate. The dihedral angles between the benzene rings in the two mol-ecules are 37.8 (2) and 35.0 (2)°.

Synthesis, cytotoxicity, antioxidant activity and molecular modeling of new NSAIDs-EBS derivatives.

Two series of NSAIDs-EBS derivatives (5a-j and 9a-i) based on the hybridization of nonsteroidal anti-inflammatory drugs (NSAIDs) skeleton and Ebselen moiety were synthesized. Their cytotoxicity was evaluated against five types of human cancer cell lines, BGC-823 (human gastric cancer cell line), SW480 (human colon adenocarcinoma cells), MCF-7 (human breast adenocarcinoma cells), HeLa (human cervical cancer cells), A549 (human lung carcinoma cells). Moreover, the most active compound 5j showed IC50 values below 3 µM in all cancer cell lines and with remarkable anticancer activity against MCF-7 (1.5 µM) and HeLa (1.7 µM). The redox properties of the NSAIDs-EBS derivatives prepared herein were conducted by 2, 2-didiphenyl-1-picrylhydrazyl (DPPH), bleomycin dependent DNA damage and glutathione peroxidase (GPx)-like assays. Finally, TrxR1 inhibition activity assay and molecular docking study revealed NSAIDs-EBS derivatives could serve as potential TrxR1 inhibitor.

Identification of sulfated metabolites of 4-chlorobiphenyl (PCB3) in the serum and urine of male rats.

Polychlorinated biphenyls (PCBs) are legacy pollutants that exert toxicities through various mechanisms. In recent years exposure to PCBs via inhalation has been recognized as a hazard. Those PCBs with lower numbers of chlorine atoms (LC-PCBs) are semivolatile and have been reported in urban air, as well as in the indoor air of older buildings. LC-PCBs are bioactivated to phenols and further to quinone electrophiles with genotoxic/carcinogenic potential. We hypothesized that phenolic LC-PCBs are subject to conjugation and excretion in the urine. PCB3, often present in high concentrations in air, is a prototypical congener for the study of the metabolism and toxicity of LC-PCBs. Our objective was to identify metabolites of PCB3 in urine that could be potentially employed in the estimation of exposure to LC-PCBs. Male Sprague-Dawley rats (150-175 g) were housed in metabolism cages and received a single intraperitoneal injection of 600 µmol/kg body weight of PCB3. Urine was collected every 4 h; rats were euthanized at 36 h; and serum was collected. LC/MS analysis of urine before and after incubation with ß-glucuronidase and sulfatase showed that sulfate conjugates were in higher concentrations than glucuronide conjugates and free phenolic forms. At least two major metabolites and two minor metabolites were identified in urine that could be attributed to mercapturic acid metabolites of PCB3. Quantitation by authentic standards confirmed that approximately 3% of the dose was excreted in the urine as sulfates over 36 h, with peak excretion occurring at 10-20 h after exposure. The major metabolites were 4'PCB3sulfate, 3'PCB3 sulfate, 2'PCB3 sulfate, and presumably a catechol sulfate. The serum concentration of 4'PCB3 sulfate was 6.18 ± 2.16 µg/mL. This is the first report that sulfated metabolites of PCBs are formed in vivo. These findings suggest a prospective approach for exposure assessment of LC-PCBs by analysis of phase II metabolites in urine.

Novel organoselenides (NSAIDs-Se derivatives) protect against LPS-induced inflammation in microglia by targeting the NOX2/NLRP3 signaling pathway.

Neuro-inflammation is an immune response of the central nervous system (CNS) to pathogens, and it is associated with a variety of neurodegenerative diseases. Microglial cells are the main category of macrophages in the CNS parenchyma, and they represent one of the most important cellular drivers and regulators of neuroinflammation. In this study, nine new organoselenium compounds based on the hybridization of nonsteroidal anti-inflammatory drugs (NSAIDs) skeleton and organoselenium motif (-SeCN and -SeCF3) were synthesized and their potential anti-neuroinflammatory effects were evaluated using LPS-induced BV2 mouse microglia. The cells were first treated with the organoselenium compounds and the extent of oxidative stress and inflammatory response of the cells was determined by measuring the levels of NO, ROS, IL-1ß, and IL-18. Among the nine compounds, 1-39 and 1A-38 exhibited the most significant effect on oxidative stress and inflammatory response. Subsequent studies carried out with 1-39 and 1A-38 showed that both compounds could reduce the production of ROS in the cells, probably through down-regulating NOX2 and its downstream targets, including TXNIP (thioredoxin-interacting protein) and NLRP3 (NOD-like receptor protein 3). In addition, 1-39 and 1A-38 also suppressed the ability of the cells to secret IL-18 and IL-1ß, which greatly dampened the response of the cells to LPS-induced inflammation. Our finding demonstrated that organoselenium compounds derived from NSAID might play an important role in the protection of brain microglia against inflammation-related neurodegenerative disease by potentially down-regulating the NOX2/NLRP3 signaling axis.

New organoselenides (NSAIDs-Se derivatives) as potential anticancer agents: Synthesis, biological evaluation and in silico calculations.

Herein we reported the synthesis of twenty new organoselenium compounds (2a-2j and 3a-3j) based on the hybridization of nonsteroidal antiinflammatory drugs (NSAIDs) skeleton and organoselenium motif (-SeCN and -SeCF3), the anticancer activity was evaluated against four types of cancer cell lines, Caco-2 (human colon adenocarcinoma cells), BGC-823 (human gastric cancer cells), MCF-7 (human breast adenocarcinoma cells), PC-3 (human prostatic cancer cells). Interestingly, the introduction of the -SeCN or -SeCF3 moiety in corresponding parent NSAIDs results in the significant effect on cancer cell lines. Moreover, the most active compound 3a showed IC50 values lower than 5 µM against the four cancer cell lines, particularly to BGC-823 and MCF-7 with IC50 values of 2.5 and 2.7 µM, respectively. Furthermore, three compounds 3a, 3g and 3i were selected to investigate their ability to induce apoptosis in BGC-823 cells via modulating the expression of anti-apoptotic Bcl-2 protein, pro-inflammatory cytokines (IL-2) and proapoptotic caspase-8 protein. The redox properties of the NSAIDs-Se derivatives prepared herein were conducted by 2, 2-didiphenyl-1-picrylhydrazyl (DPPH), bleomycin dependent DNA damage and glutathione peroxidase (GPx)-like assays. Finally, molecular docking study revealed that an interaction with the active site of thioredoxin reductase 1 (TrxR1) and predicted the anticancer activity of the synthesized candidates. Overall, these results could serve a promising launch point for further design of NSAIDs-Se derivatives as potential anticancer agents.

Aesculetin-induced apoptosis through a ROS-mediated mitochondrial dysfunction pathway in human cervical cancer cells.

Aesculetin (1) is an important coumarin found in various plant materials. It has been shown to have antiproliferative effects on several types of human cancer cells, but its effect on cervical cancer cells in vitro is unknown. In this study, we investigated that the cytotoxic effect of 1 on a non-cancer cell line (293) was smaller than on a tumor cell line (HeLa). This is the first report showing the possible mechanism of antiproliferative effect of 1 for the prevention of cervical cancer in cell culture models. It was found that 1 inhibited cell viability by inducing apoptosis, as evidenced by the formation of apoptotic bodies, generation of reactive oxygen species (ROS), and the accumulation of cells in the sub-G1 phase. Treatment with compound 1 decreased the cell growth in a dose-dependent manner with an IC(50) value of 37.8 microM. Aesculetin-induced apoptosis was correlated with mitochondrial dysfunction (DeltaPsi(m)), leading to the release of cytochrome c from the mitochondria to the cytosol, as well as the proteolytic activation of caspases in HeLa cells. These results indicate that 1 induces apoptosis in HeLa cells through a ROS-mediated mitochondrial dysfunction pathway.

Recent Advances of Chitosan and its Derivatives in Biomedical Applications.

Chitosan is the second-most abundant natural polysaccharide. It has unique characteristics, such as biodegradability, biocompatibility, and non-toxicity. Due to the existence of its free amine group and hydroxyl groups on its backbone chain, chitosan can undergo further chemical modifications to generate Chitosan Derivatives (CDs) that permit additional biomedical functionality. Chitosan and CDs can be fabricated into various forms, including Nanoparticles (NPs), micelles, hydrogels, nanocomposites and nano-chelates. For these reasons, chitosan and CDs have found a tremendous variety of biomedical applications in recent years. This paper mainly presents the prominent applications of chitosan and CDs for cancer therapy/diagnosis, molecule biosensing, viral infection, and tissue engineering over the past five years. Moreover, future research directions on chitosan are also considered.

Synthesis and biological evaluation of organoselenium (NSAIDs-SeCN and SeCF3) derivatives as potential anticancer agents.

A series of organoselenium compounds based on the hybridization of nonsteroidal antiinflammatory drugs (NSAIDs) scaffolds and Se functionalities (-SeCN and -SeCF3) were synthesized and characterized, and evaluated against four types of cancer cell lines, SW480 (human colon adenocarcinoma cells), HeLa (human cervical cancer cells), A549 (human lung carcinoma cells), MCF-7 (human breast adenocarcinoma cells). Interestingly, most of the investigated compounds showed active in reducing the viability of different cancer cell lines. The most active compound 3h showed IC50 values lower than 20 µM against the four cancer cell lines, particularly to SW480 and MCF-7 with IC 50 values of 4.9 and 3.4 µM, respectively. Furthermore, NSAIDs-SeCN derivatives (2h and 2i) and NSAIDs-SeCF3 derivatives (3h and 3i) were selected to investigate their ability to induce apoptosis in MCF-7 cells via modulation the expression of anti-apoptotic Bcl-2 protein, pro-inflammatory cytokines (IL-2) and proapoptotic caspase-3 protein. Moreover, the redox properties of the synthesized organoselenium candidates were conducted by 2, 2-didiphenyl-1-picrylhydrazyl (DPPH), bleomycin dependent DNA damage and glutathione peroxidase (GPx)-like assays. Taken together, these NSAIDs-Se candidates could provide promising new lead derivatives for further potential anticancer drug development.

Theranostic Applications of Antibody-Based Systems in Human Diseases.

Since antibodies are one of the most successful classes of biopharmaceuticals for cancer treatment, it is very important to discuss the functionality and biological activity of endogenous antibodies in the diagnosis and treatment of the diseases. Antibodies act on tumor cells in diverse ways, including engaging in antibody-dependent effector mechanisms, internalizing to deliver toxins, and displaying direct effects on cells. In this review, we outline three kinds of antibody-based therapeutic systems, namely Antibody-based Drug Conjugates (Ab-DCs), Antibody-based Recruiting Small Molecules (Ab-RSMs) and Carbohydrate Epitopes Recruiting Natural Antibodies (CERNA) for human disease treatment and imaging. These antibody-based therapeutic systems are able to strengthen the binding ability of antibodies with disease-relevant cells or viruses, leading to their immuno-mediated therapeutic responses and clearance. Research in these fields shows exciting potential at the junction of organic chemistry and immune-biology. Since the applications of antibodies are of great importance, it is necessary to functionalize antibodies or develop other antibody-based synthetic strategies to modulate the human immune system, and ultimately achieve the treatment of diseases.

In Vivo Targeting and Positron Emission Tomography Imaging of Tumor with Intrinsically Radioactive Metal-Organic Frameworks Nanomaterials.

Nanoscale metal-organic frameworks (nMOF) materials represent an attractive tool for various biomedical applications. Due to the chemical versatility, enormous porosity, and tunable degradability of nMOFs, they have been adopted as carriers for delivery of imaging and/or therapeutic cargos. However, the relatively low stability of most nMOFs has limited practical in vivo applications. Here we report the production and characterization of an intrinsically radioactive UiO-66 nMOF (89Zr-UiO-66) with incorporation of positron-emitting isotope zirconium-89 (89Zr). 89Zr-UiO-66 was further functionalized with pyrene-derived polyethylene glycol (Py-PGA-PEG) and conjugated with a peptide ligand (F3) to nucleolin for targeting of triple-negative breast tumors. Doxorubicin (DOX) was loaded onto UiO-66 with a relatively high loading capacity (1 mg DOX/mg UiO-66) and served as both a therapeutic cargo and a fluorescence visualizer in this study. Functionalized 89Zr-UiO-66 demonstrated strong radiochemical and material stability in different biological media. Based on the findings from cellular targeting and in vivo positron emission tomography (PET) imaging, we can conclude that 89Zr-UiO-66/Py-PGA-PEG-F3 can serve as an image-guidable, tumor-selective cargo delivery nanoplatform. In addition, toxicity evaluation confirmed that properly PEGylated UiO-66 did not impose acute or chronic toxicity to the test subjects. With selective targeting of nucleolin on both tumor vasculature and tumor cells, this intrinsically radioactive nMOF can find broad application in cancer theranostics.

Estrogenicity and androgenicity screening of PCB sulfate monoesters in human breast cancer MCF-7 cells.

Recent studies identified polychlorinated biphenyl (PCB) sulfate esters as a major product of PCB metabolism. Since hydroxy-PCBs (HO-PCBs), the immediate precursors of PCB sulfates and important contributors to PCB toxicity, were shown to have estrogenic activity, we investigated the estrogenicity/androgenicty of a series of PCB sulfate metabolites. We synthesized the five possible structural sulfate monoester metabolites of PCB 3, a congener shown to be biotransformed to sulfates, a sulfate ester of the paint-specific congener PCB 11, and sulfate monoesters of two HO-PCBs reported to interact with sulfotransferases (PCB 39, no ortho chlorines, and PCB 53, 3 ortho chlorines). We tested these PCB sulfates and 4'-HO-PCB 3 as positive control for estrogenic, androgenic, anti-estrogenic, and anti-androgenic activity in the E- and A-screen with human breast cancer MCF7-derived cells at 100 µM-1 pM concentrations. Only 4'-HO-PCB 3 was highly cytotoxic at 100 µM. We observed structure-activity relationships: compounds with a sulfate group in the chlorine-containing ring of PCB 3 (2PCB 3 and 3PCB 3 sulfate) showed no interaction with the estrogen (ER) and androgen (AR) receptor. The 4'-HO-PCB 3 and its sulfate ester had the highest estrogenic effect, but at 100-fold different concentrations, i.e., 1 and 100 µM, respectively. Four of the PCB sulfates were estrogenic (2'PCB 3, 4'PCB 3, 4'PCB 39, and 4'PCB 53 sulfates; at 100 µM). These sulfates and 3'PCB 3 sulfate also exhibited anti-estrogenic activity, but at nM and pM concentrations. The 4'PCB 3 sulfate (para-para' substituted) had the strongest androgenic activity, followed by 3'PCB 3, 4'PCB 53, 4PCB11, and 4PCB 39 sulfates and the 4'HO-PCB 3. In contrast, anti-androgenicity was only observed with the two compounds that have the sulfate group in ortho- or meta- position in the second ring (2'PCB 3 and 3'PCB 3 sulfate). No dose-response was observed in any screen, but, with exception of estrogenic activity (only seen at 100 µM), endocrine activity was often displayed at several concentrations and even at 1 pM concentration. These data suggest that sulfation of HO-PCBs is indeed reducing their cytotoxicity and estrogenicity, but may produce other endocrine disruptive activities at very low concentrations.

Modulating inhibitors of transthyretin fibrillogenesis via sulfation: polychlorinated biphenyl sulfates as models.

Small molecules that bind with high affinity to thyroxine (T4) binding sites on transthyretin (TTR) kinetically stabilize the protein's tetrameric structure, thereby efficiently decreasing the rate of tetramer dissociation in TTR related amyloidoses. Current research efforts aim to optimize the amyloid inhibiting properties of known inhibitors, such as derivatives of biphenyls, dibenzofurans and benzooxazoles, by chemical modification. In order to test the hypothesis that sulfate group substituents can improve the efficiencies of such inhibitors, we evaluated the potential of six polychlorinated biphenyl sulfates to inhibit TTR amyloid fibril formation in vitro. In addition, we determined their binding orientations and molecular interactions within the T4 binding site by molecular docking simulations. Utilizing this combined experimental and computational approach, we demonstrated that sulfation significantly improves the amyloid inhibiting properties as compared to both parent and hydroxylated PCBs. Importantly, several PCB sulfates were of equal or higher potency than some of the most effective previously described inhibitors.

Synthesis and anticonvulsant activity of ethyl 2,2-dimethyl-1-(2-substitutedhydrazinecarboxamido) cyclopropanecarboxylate derivatives.

In this study on the development of new anticonvulsants, fourteen ethyl 2,2-dimethyl-1-(2-substitutedhydrazinecarboxamido) cyclopropanecarboxylate derivatives were synthesized and tested for anticonvulsant activity using the maximal electroshock, subcutaneous pentylenetetrazole screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotorod test. Two compounds 6f and 6k showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 6k showed the maximal electroshock-induced seizures with ED50 value of 9.2 mg/kg and TD50 value of 387.5 mg/kg after intraperitoneally injection to mice, which provided compound 6k with a protective index (TD50/ED50 ) of 42.1 in the maximal electroshock test.

Total synthesis of a sialyl Lewis(x) derivative for the diagnosis of cancer.

The total synthesis of aminoethyl glycoside of sialyl Lewis(x) (sLe(x)) is described. A galactose donor was condensed with a diol of glucosamine to afford regioselectively a ß1,4 linked disaccharide, which was further stereoselectively fucosylated to provide a protected Lewis(x) trisaccharide. After chemical modification, the trisaccharide was sialylated to give regio- and stereoselectively an azidoethyl glycoside of sLe(x). Finally, deprotection and azide reduction afforded the target compound. This compound will be coupled with protein and then be used to conduct further preclinical studies for the diagnosis of cancer.