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1.
RSC Med Chem ; 15(5): 1737-1745, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38784458

ABSTRACT

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.

2.
Eur J Med Chem ; 259: 115662, 2023 Nov 05.
Article in English | MEDLINE | ID: mdl-37482018

ABSTRACT

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.


Subject(s)
Adenocarcinoma , Anti-Inflammatory Agents, Non-Steroidal , Antineoplastic Agents , Humans , Antineoplastic Agents/chemistry , Antioxidants/pharmacology , Cell Line, Tumor , Cell Proliferation , Colonic Neoplasms , Drug Screening Assays, Antitumor , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology
3.
Molecules ; 27(14)2022 Jul 06.
Article in English | MEDLINE | ID: mdl-35889201

ABSTRACT

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.


Subject(s)
Adenocarcinoma , Antineoplastic Agents , Colonic Neoplasms , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/chemistry , Apoptosis , Cell Line, Tumor , Cell Proliferation , Drug Screening Assays, Antitumor , Humans , Molecular Docking Simulation , Molecular Structure , Organoselenium Compounds , Structure-Activity Relationship , Urea/analogs & derivatives
4.
Int Immunopharmacol ; 101(Pt B): 108377, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34836795

ABSTRACT

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.


Subject(s)
Inflammation/chemically induced , Lipopolysaccharides/toxicity , Microglia/drug effects , NADPH Oxidase 2/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Organoselenium Compounds/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cytokines/genetics , Cytokines/metabolism , Gene Expression Regulation/drug effects , Mice , Molecular Structure , NADPH Oxidase 2/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Organoselenium Compounds/chemistry , Signal Transduction/drug effects
5.
Eur J Med Chem ; 218: 113384, 2021 Jun 05.
Article in English | MEDLINE | ID: mdl-33799070

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Organoselenium Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Organoselenium Compounds/chemical synthesis , Organoselenium Compounds/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured
6.
Eur J Med Chem ; 208: 112864, 2020 Dec 15.
Article in English | MEDLINE | ID: mdl-32987314

ABSTRACT

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.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/pharmacology , Organoselenium Compounds/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Apoptosis/drug effects , Caspase 3/metabolism , Cell Line, Tumor , DNA/drug effects , DNA Damage/drug effects , Drug Screening Assays, Antitumor , Free Radical Scavengers/chemical synthesis , Free Radical Scavengers/metabolism , Free Radical Scavengers/pharmacology , Humans , Interleukin-2/metabolism , Molecular Docking Simulation , Organoselenium Compounds/chemical synthesis , Organoselenium Compounds/metabolism , Protein Binding , Proto-Oncogene Proteins c-bcl-2/metabolism , Thioredoxin Reductase 1/metabolism
7.
Chem Biodivers ; 17(5): e1900603, 2020 May.
Article in English | MEDLINE | ID: mdl-32198823

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Cyanates/pharmacology , Organoselenium Compounds/pharmacology , Selenium Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cyanates/chemical synthesis , Cyanates/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Organoselenium Compounds/chemical synthesis , Organoselenium Compounds/chemistry , Selenium Compounds/chemical synthesis , Selenium Compounds/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured
8.
Curr Med Chem ; 27(18): 3023-3045, 2020.
Article in English | MEDLINE | ID: mdl-30961477

ABSTRACT

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.


Subject(s)
Chitosan/metabolism , Nanocomposites , Nanoparticles , Hydrogels , Tissue Engineering
9.
J Biomed Nanotechnol ; 14(3): 405-429, 2018 Mar 01.
Article in English | MEDLINE | ID: mdl-29663918

ABSTRACT

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.


Subject(s)
Theranostic Nanomedicine , Antibodies , Humans , Viruses
10.
Bioorg Med Chem Lett ; 27(18): 4256-4269, 2017 09 15.
Article in English | MEDLINE | ID: mdl-28803753

ABSTRACT

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.


Subject(s)
Aptamers, Nucleotide/chemistry , Biomedical Research , Neoplasms/diagnosis , Animals , Biosensing Techniques , Drug Delivery Systems , Genetic Therapy , Humans
11.
ACS Nano ; 11(4): 4315-4327, 2017 04 25.
Article in English | MEDLINE | ID: mdl-28345871

ABSTRACT

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.


Subject(s)
Drug Carriers/chemistry , Metal-Organic Frameworks/chemistry , Nanoparticles/chemistry , Neoplasms/diagnostic imaging , Neoplasms/therapy , Radiopharmaceuticals/chemistry , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Cell Line , Cell Line, Tumor , Contrast Media/chemistry , Doxorubicin/administration & dosage , Doxorubicin/chemistry , Drug Liberation , Female , Humans , Metal-Organic Frameworks/toxicity , Mice, Inbred BALB C , Molecular Targeted Therapy , Peptides/chemistry , Polyethylene Glycols/chemistry , Positron-Emission Tomography , Radioisotopes/chemistry , Tissue Distribution , Zirconium/chemistry
12.
Environ Sci Pollut Res Int ; 23(3): 2186-200, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26300354

ABSTRACT

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.


Subject(s)
Androgens/pharmacology , Breast Neoplasms/metabolism , Estrogens/pharmacology , Polychlorinated Biphenyls/pharmacology , Androgens/metabolism , Esters/metabolism , Esters/pharmacology , Estrogen Antagonists/metabolism , Estrogen Antagonists/pharmacology , Estrogens/metabolism , Female , Humans , MCF-7 Cells , Polychlorinated Biphenyls/metabolism , Receptors, Androgen/metabolism , Receptors, Estrogen/metabolism , Sulfates/metabolism , Sulfates/pharmacology
13.
Environ Sci Technol ; 49(13): 8087-95, 2015 Jul 07.
Article in English | MEDLINE | ID: mdl-26046945

ABSTRACT

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.


Subject(s)
Polychlorinated Biphenyls/metabolism , Animals , Bile/chemistry , Bile/metabolism , Chromatography, Liquid , Injections, Intravenous , Male , Polychlorinated Biphenyls/chemistry , Polychlorinated Biphenyls/isolation & purification , Rats, Sprague-Dawley , Spectrometry, Mass, Electrospray Ionization , Tissue Distribution
14.
Chem Biol Interact ; 228: 1-8, 2015 Feb 25.
Article in English | MEDLINE | ID: mdl-25595224

ABSTRACT

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.


Subject(s)
Amyloid/antagonists & inhibitors , Prealbumin/metabolism , Sulfates/chemistry , Sulfates/pharmacology , Amyloid/metabolism , Humans , Molecular Docking Simulation , Molecular Structure , Prealbumin/antagonists & inhibitors , Structure-Activity Relationship
15.
Atmos Environ (1994) ; 94: 366-373, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-24976783

ABSTRACT

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.

16.
Eur J Med Chem ; 75: 247-57, 2014 Mar 21.
Article in English | MEDLINE | ID: mdl-24534540

ABSTRACT

A concise and efficient synthetic route for preparation of four ganglioside GM3 analogues was described. The key step is a highly regioselective and stereoselective α-sialylation from a suitably protected glycoside acceptor with a sialyl xanthate to provide the sialo-oligosaccharide in good yield. The cytotoxic properties of the synthetic gangliosides were evaluated against normal human keratinocytes and human HCT116 and K562 cancer cells. Two of them exhibited good antiproliferative activity and displayed a better cytotoxicity against cancer cell than HaCaT normal cell.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , G(M3) Ganglioside/analogs & derivatives , G(M3) Ganglioside/pharmacology , N-Acetylneuraminic Acid/chemistry , N-Acetylneuraminic Acid/pharmacology , Antineoplastic Agents/chemical synthesis , Cell Line , Cell Line, Tumor , Cytotoxins/chemical synthesis , Cytotoxins/chemistry , Cytotoxins/pharmacology , G(M3) Ganglioside/chemical synthesis , Humans , Keratinocytes/drug effects , N-Acetylneuraminic Acid/chemical synthesis , Neoplasms/drug therapy , Neoplasms/pathology
17.
Chem Biol Drug Des ; 84(2): 234-41, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24571574

ABSTRACT

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.


Subject(s)
Anticonvulsants/chemistry , Anticonvulsants/therapeutic use , Cyclopropanes/chemistry , Cyclopropanes/therapeutic use , Seizures/drug therapy , Animals , Anticonvulsants/chemical synthesis , Cyclopropanes/chemical synthesis , Electroshock , Male , Mice , Rotarod Performance Test
18.
Carbohydr Res ; 383: 89-96, 2014 Jan 13.
Article in English | MEDLINE | ID: mdl-24333940

ABSTRACT

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.


Subject(s)
E-Selectin/chemistry , Neoplasms/diagnosis , Oligosaccharides/chemical synthesis , Trisaccharides/chemical synthesis , E-Selectin/isolation & purification , Glucosamine/chemistry , Humans , Ligands , Neoplasms/pathology , Oligosaccharides/chemistry , Sialyl Lewis X Antigen , Trisaccharides/chemistry
19.
Chemosphere ; 93(9): 1965-71, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23906814

ABSTRACT

Chlorophenols are an important class of persistent environmental contaminants and have been implicated in a range of adverse health effects, including cancer. They are readily conjugated and excreted as the corresponding glucuronides and sulfates in the urine of humans and other species. Here we report the synthesis and characterization of a series of ten chlorophenol sulfates by sulfation of the corresponding chlorophenols with 2,2,2-trichloroethyl (TCE) chlorosulfate using N,N-dimethylaminopyridine (DMAP) as base. Deprotection of the chlorophenol diesters with zinc powder/ammonium formate yielded the respective chlorophenol sulfate ammonium salts in good yield. The molecular structure of three TCE-protected chlorophenol sulfate diesters and one chlorophenol sulfate monoester were confirmed by X-ray crystal structure analysis. The chlorophenol sulfates were stable for several months if stored at -20 °C and, thus, are useful for future toxicological, environmental and human biomonitoring studies.


Subject(s)
Chlorophenols/metabolism , Environmental Pollutants/metabolism , Models, Chemical , Phenols/metabolism , Sulfates/metabolism , Biodegradation, Environmental , Chlorophenols/analysis , Environmental Monitoring , Environmental Pollutants/analysis , Phenols/analysis , Sulfates/analysis
20.
Acta Crystallogr Sect E Struct Rep Online ; 69(Pt 4): o620, 2013 Apr 01.
Article in English | MEDLINE | ID: mdl-23634142

ABSTRACT

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)°.

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