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Environment International Jul 2020Exposure to per-/polyfluoroalkyl substances (PFASs) can disrupt endocrine hormones in humans. Prior studies have focused on the harmful effects of the two traditional...
BACKGROUND
Exposure to per-/polyfluoroalkyl substances (PFASs) can disrupt endocrine hormones in humans. Prior studies have focused on the harmful effects of the two traditional per-/polyfluoroalkyl substances (PFASs), perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). Other PFASs, used as the replacements of PFOS and PFOA, are widely and increasingly detected in humans. Whether these replacements influence glucocorticoids and progestogens in newborns remains unknown.
OBJECTIVE
To investigate the associations between exposures of PFOS, PFOA and their replacements and glucocorticoids and progestogens in newborns.
METHODS
We measured the concentrations of 13 PFASs, 3 glucocorticoids (11-deoxycortisol, cortisol and cortisone) and 2 progestogens [progesterone, 17-hydroxyprogesterone (17OHP)] in the cord sera of 374 neonates in a birth cohort from Wuhan, China, between 2013 and 2014. We evaluated the associations of each PFAS with glucocorticoids and progestogens using multiple linear regression models, and multiple comparisons were additionally corrected via false discovery rates (FDR).
RESULTS
Out of the 13 PFASs, 9 were detected in over 95% of cord sera. The Chinese specific PFOS replacement - 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA, trade name F-53B) was positively associated with 13.13% change in cortisol in girls (95% CI = 4.47%, 22.52%, for each IQR increase in 6:2 Cl-PFESA). Seven PFASs had positive associations with the precursor of cortisol, namely 11-deoxycortisol (percent change ranged from 6.41% to 11.24%, for each IQR increase in PFASs). Perfluorobutane sulfonate (PFBS) in cord sera was positively associated with progesterone in the linear model, whereas PFOS and perfluorohexane sulfonate (PFHxS) levels were associated with progesterone in the quartile models. No PFASs were related to 17OHP or cortisone.
CONCLUSIONS
In this study, PFOS, PFOA and/or their replacements were positively associated with progesterone, cortisol and 11-deoxycortisol in newborns. These results suggested that not only PFOS and PFOA, but also other PFASs have potential impacts on glucocorticoids and progestogens in newborns.
Topics: Alkanesulfonates; Alkanesulfonic Acids; Caprylates; China; Environmental Pollutants; Ethers; Female; Fluorocarbons; Glucocorticoids; Humans; Infant, Newborn; Progestins
PubMed: 32474218
DOI: 10.1016/j.envint.2020.105636 -
Advances in Carbohydrate Chemistry and... 2020Increasing demands for molecules with skeletal complexity, including those of stereochemical diversity, require new synthetic strategies. Carbohydrates have been used...
Vinyl sulfone-modified carbohydrates: Michael acceptors and 2π partners for the synthesis of functionalized sugars and enantiomerically pure carbocycles and heterocycles.
Increasing demands for molecules with skeletal complexity, including those of stereochemical diversity, require new synthetic strategies. Carbohydrates have been used extensively as chiral building blocks for the synthesis of various complex molecules. On the other hand, the vinyl sulfone group has been identified as a unique functional group, which acts either as a Michael acceptor or a 2π partner in cycloaddition reactions. A combination of the high reactivity of the vinyl sulfone group and the in-built chiralities of carbohydrates has the potential to function as a powerful tool to generate a wide variety of enantiomerically pure reactive intermediates. Since CS bond formation in carbohydrates is easily achieved with regioselectivity, further synthetic manipulations of these thiosugars has led to the generation of a wide range of vinyl sulfone-modified furanosyl, pyranosyl, acyclic, and bicyclic carbohydrates. Several approaches have been studied to standardize the preparative methods for accessing vinyl sulfone-modified carbohydrates at least on a gram scale. Reactions of these modified carbohydrates with appropriate reagents afford a large number of new chemical entities primarily via (i) Michael addition reactions, (ii) desulfostannylation, (iii) Michael-initiated ring-closure reactions, and (iv) cycloaddition reactions. A wide range of desulfonylating reagents in the context of sensitive molecules such as carbohydrates have also been extensively studied. Applications of these strategies have led to the synthesis of (a) amino sugars and branched-chain sugars, (b) C-glycosides, (c) enantiomerically pure cyclopropanes, five- and six-membered carbocycles, (d) saturated oxa-, aza-, and thio-monocyclic heterocycles, (e) bi-and tricyclic saturated oxa and aza heterocycles, (f) enantiomerically pure and trisubstituted pyrroles, (g) 1,5-disubstituted 1,2,3-triazolylated carbohydrates and the corresponding triazole-linked di- and trisaccharides, (h) divinyl sulfone-modified carbohydrates and densely functionalized S,S-dioxothiomorpholines, and (i) modified nucleosides. Details of reaction conditions were incorporated as much as possible and mechanistic discussions were included wherever necessary.
Topics: Acids, Carbocyclic; Amino Sugars; Carbohydrates; Chemistry Techniques, Synthetic; Cycloaddition Reaction; Glycosides; Heterocyclic Compounds; Humans; Morpholines; Nucleosides; Pyrroles; Stereoisomerism; Sulfones; Triazoles
PubMed: 33276909
DOI: 10.1016/bs.accb.2020.10.001 -
Cancer Medicine Feb 2024It has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth....
BACKGROUND
It has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth. Additionally, acidosis in the TME has been reported to play a key role in selecting for a more aggressive tumor phenotype, drug resistance and desensitization to immunotherapy for many types of cancers. TME-HAP is an attractive target for tumor detection and treatment development since HAP is generally absent from normal soft tissue. We provide strong evidence that dissolution of hydroxyapatite (HAP) within the tumor microenvironment (TME-HAP) using a novel therapeutic can be used to kill cancer cells both in vitro and in vivo with minimal adverse effects.
METHODS
We developed an injectable cation exchange nano particulate sulfonated polystyrene solution (NSPS) that we engineered to dissolve TME-HAP, inducing localized acute alkalosis and inhibition of tumor growth and glucose metabolism. This was evaluated in cell culture using 4T1, MDA-MB-231 triple negative breast cancer cells, MCF10 normal breast cells, and H292 lung cancer cells, and in vivo using orthotopic mouse models of cancer that contained detectable microenvironment HAP including breast (MMTV-Neu, 4T1, and MDA-MB-231), prostate (PC3) and colon (HCA7) cancer using F-NaF for HAP and F-FDG for glucose metabolism with PET imaging. On the other hand, H292 lung tumor cells that lacked detectable microenvironment HAP and MCF10a normal breast cells that do not produce HAP served as negative controls. Tumor microenvironment pH levels following injection of NSPS were evaluated via Chemical Exchange Saturation (CEST) MRI and via ex vivo methods.
RESULTS
Within 24 h of adding the small concentration of 1X of NSPS (~7 μM), we observed significant tumor cell death (~ 10%, p < 0.05) in 4T1 and MDA-MB-231 cell cultures that contain HAP but ⟨2% in H292 and MCF10a cells that lack detectable HAP and in controls. Using CEST MRI, we found extracellular pH (pHe) in the 4T1 breast tumors, located in the mammary fat pad, to increase by nearly 10% from baseline before gradually receding back to baseline during the first hour post NSPS administration. in the tumors that contained TME-HAP in mouse models, MMTV-Neu, 4T1, and MDA-MB-231, PC3, and HCA7, there was a significant reduction (p<0.05) in F-Na Fuptake post NSPS treatment as expected; F uptake in the tumor = 3.8 ± 0.5 %ID/g (percent of the injected dose per gram) at baseline compared to 1.8 ±0.5 %ID/g following one-time treatment with 100 mg/kg NSPS. Of similar importance, is that F-FDG uptake in the tumors was reduced by more than 75% compared to baseline within 24 h of treatment with one-time NSPS which persisted for at least one week. Additionally, tumor growth was significantly slower (p < 0.05) in the mice treated with one-time NSPS. Toxicity showed no evidence of any adverse effects, a finding attributed to the absence of HAP in normal soft tissue and to our therapeutic NSPS having limited penetration to access HAP within skeletal bone.
CONCLUSION
Dissolution of TME-HAP using our novel NSPS has the potential to provide a new treatment paradigm to enhance the management of cancer patients with poor prognosis.
Topics: Humans; Male; Animals; Mice; Pharmaceutical Preparations; Fluorodeoxyglucose F18; Immunotherapy; Drug-Related Side Effects and Adverse Reactions; Lung Neoplasms; Alkanesulfonates; Glucose; Hydroxyapatites; Tumor Microenvironment
PubMed: 38239047
DOI: 10.1002/cam4.6812 -
Molecules (Basel, Switzerland) Jan 2022Natural plant compounds, such as betaine, are described to have nematocidal properties. Betaine also acts as a neurotransmitter in the free-living model nematode , where...
Natural plant compounds, such as betaine, are described to have nematocidal properties. Betaine also acts as a neurotransmitter in the free-living model nematode , where it is required for normal motility. Worm motility is mediated by nicotinic acetylcholine receptors (nAChRs), including subunits from the nematode-specific DEG-3 group. Not all types of nAChRs in this group are associated with motility, and one of these is the DEG-3/DES-2 channel from , which is involved in nociception and possibly chemotaxis. Interestingly, the activity of DEG-3/DES-2 channel from the parasitic nematode of ruminants, , is modulated by monepantel and its sulfone metabolite, which belong to the amino-acetonitrile derivative anthelmintic drug class. Here, our aim was to advance the pharmacological knowledge of the DEG-3/DES-2 channel from by functionally expressing the DEG-3/DES-2 channel in oocytes and using two-electrode voltage-clamp electrophysiology. We found that the DEG-3/DES-2 channel was more sensitive to betaine than ACh and choline, but insensitive to monepantel and monepantel sulfone when used as direct agonists and as allosteric modulators in co-application with betaine. These findings provide important insight into the pharmacology of DEG-3/DES-2 from and highlight the pharmacological differences between non-parasitic and parasitic nematode species.
Topics: Aminoacetonitrile; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; GABA Plasma Membrane Transport Proteins; Ion Channel Gating; Membrane Potentials; Receptors, Nicotinic; Sulfones; Xenopus laevis
PubMed: 35011544
DOI: 10.3390/molecules27010312 -
Scientific Reports Dec 2022Novel polyelectrolytic hybrid membranes are prepared by blending carboxy methyl cellulose (CMC)-polyvinyl alcohol (PVA)-acrylamide (AA). Succinic acid and chlorosulfonic...
Novel polyelectrolytic hybrid membranes are prepared by blending carboxy methyl cellulose (CMC)-polyvinyl alcohol (PVA)-acrylamide (AA). Succinic acid and chlorosulfonic acid (CSA) are employed as crosslinkers and modifiers, respectively. Additionally, carboxylated carbon nanotube (CCNT) and sulfonated activated carbon (SAC) as fillers are used to attain appropriate chemical and mechanical stability for use as polyelectrolyte membranes (PEM). CMC, PVA, and AA are mixed and treated with CSA, CCNT, and SAC in different concentrations. First, CMC/PVA/AA solution is modified using CSA to produce a sulfonated polymeric matrix. Second, a different amount of CCNT or SAC was added as a filler to enhance the ion exchange capacity (IEC), ionic conductivity, and chemical stability. Third, the solution is cast as polyelectrolytic membranes. Chemical interactions between CMC, PVA, AA and other membrane components were confirmed using various characterization techniques such as Raman scattering spectroscopy and Fourier Transform Infrared (FTIR). Furthermore, mechanical strength, methanol uptake, gel fraction, ion exchange capacity (IEC), proton conductivity (PC), chemical and thermal stability were determined as functions of varied membrane modification components. Results reveal that the increase of CSA, CCNT and SAC is leading to increase the IEC values reaching 1.54 mmol/g for (CMC/PVA-4% CSA), 1.74 mmol/g for (CMC/PVA-4%CSA-2%CCNT) and 2.31 mmol/g for (CMC/PVA-4% CSA-2% SAC) comparing to 0.11 mmol/g for non-modified CMC/PVA/AA membrane. Sequentially, the proton conductivity value is changed from 1 × 10 S/cm in non-modified CMC/PVA/AA membrane to 0.082 S/cm for (CMC/PVA-4% CSA), 0.0984 S/cm for (CMC/PVA-4%CSA-2%CCNT) and 0.1050 S/cm for (CMC/PVA-4% CSA-2% SAC). Such results enhance the potential feasibility of modified CMC/PVA/AA hybrid as polyelectrolytic membranes.
Topics: Polyvinyl Alcohol; Polyelectrolytes; Acrylamide; Carboxymethylcellulose Sodium; Protons; Alkanesulfonates
PubMed: 36539477
DOI: 10.1038/s41598-022-26489-0 -
Journal of Labelled Compounds &... Jun 2020Firocoxib (ML-1,785,713) is a nonsteroidal, potent, and selective COX-2 inhibitor, approved for the control of pain and inflammation associated with osteoarthritis in...
Firocoxib (ML-1,785,713) is a nonsteroidal, potent, and selective COX-2 inhibitor, approved for the control of pain and inflammation associated with osteoarthritis in dogs and horses, as well as to control postoperative pain and inflammation in dogs. We employed a six-step synthesis to prepare firocoxib-[ C ] in an overall yield of 35% from the commercially available bromobenzene-[ C ]. The synthetic route involved the preparation of the key intermediate phenyl- C -methyl sulfide using cesium carbonate and S-methylthiourea sulfate under transition-metal free conditions. A two-step preparation of firocoxib-[ C, H ] via the sulfinic acid derivative of firocoxib and methyl iodide-[ C, H ] using the procedure of Gauthier and Yoshikawa was first undertaken. However, the deuterium atoms of the methyl sulfone undergo extensive exchange in aqueous media even at neutral pH. The isotope-labelled firocoxib is intended as an internal standard for bioanalyses of firocoxib from biological matrices.
Topics: 4-Butyrolactone; Animals; Chemistry Techniques, Synthetic; Dogs; Horses; Isotope Labeling; Radiochemistry; Sulfones
PubMed: 32307719
DOI: 10.1002/jlcr.3842 -
Bioorganic & Medicinal Chemistry Letters Sep 2020Heroin overdose and addiction remain significant health and economic burdens in the world today costing billions of dollars annually. Moreover, only limited...
Heroin overdose and addiction remain significant health and economic burdens in the world today costing billions of dollars annually. Moreover, only limited pharmacotherapeutic options are available for treatment of heroin addiction. In our efforts to combat the public health threat posed by heroin addiction, we have developed vaccines against heroin. To expand upon our existing heroin-vaccine arsenal, we synthesized new aryl and alkyl sulfonate ester haptens; namely aryl-mono-sulfonate (H) and Aryl/alkyl-di-sulfonate (H) as carboxyl-isosteres of heroin then compared them to our model heroin-hapten (H) through vaccination studies. Heroin haptens were conjugated to the carrier protein CRM and the resulting CRM-immunoconjugates were used to vaccinate Swiss Webster mice following an established immunization protocol. Binding studies revealed that the highest affinity anti-heroin antibodies were generated by the H vaccine followed by the H and H vaccines, respectively (H > H≫H). However, neither the H nor H vaccines were able to generate high affinity antibodies to the psychoactive metabolite 6-acetyl morphine (6-AM), in comparison to the H vaccine. Blood brain bio-distribution studies supported these binding results with vaccine efficiency following the trend H > H ≫ H The work described herein provides insight into the use of hapten-isosteric replacement in vaccine drug design.
Topics: Alkanesulfonates; Animals; Antibodies; Bacterial Proteins; Brain; Drug Design; Haptens; Heroin; Mice; Vaccines, Synthetic
PubMed: 32738981
DOI: 10.1016/j.bmcl.2020.127388 -
Environmental Research Dec 2023Leakage of fire-fighting foam from an airfield caused contamination of the drinking water supplied to a third of the population in Ronneby, resulting in very high serum...
BACKGROUND
Leakage of fire-fighting foam from an airfield caused contamination of the drinking water supplied to a third of the population in Ronneby, resulting in very high serum levels of predominantly perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS). The results of studies investigating the association between exposure to perfluorinated alkyl substances (PFAS) and pregnancy complications are inconsistent, and studies at high exposures of PFOS and PFHxS are lacking.
OBJECTIVES
To investigate the association between exposure to high levels of PFAS and gestational hypertension and preeclampsia, and gestational diabetes mellitus.
METHODS
We retrieved data on 27 292 childbirths between 1995 and 2013 from the National Medical Birth Register for women that had a residential address in Blekinge county for at least one year before delivery. Residential history was used as a proxy for exposure by categorizing women into high-, intermediate-, or background exposed based on their residential address during the five-year period before childbirth. Data on confounders were retrieved from administrative registers. The outcomes were defined based on International Classification of Diseases codes. We used logistic regression to estimate odds ratios (OR) for gestational hypertension and preeclampsia, and gestational diabetes mellitus. We also investigated effect modification by fetal sex.
RESULTS
We found no evidence of increased risk of gestational hypertension and preeclampsia (OR 0.80; CI 0.63-1.03), nor gestational diabetes (OR 1.03; CI 0.67-1.58) after high PFAS exposure. There was no effect modification by fetal sex.
DISCUSSION
This was the first study to investigate the association between high exposure to PFOS and PFHxS and pregnancy complications. The results from this study add important knowledge to public health management as new hotspots with high levels of PFAS are continuously discovered.
Topics: Pregnancy; Female; Humans; Hypertension, Pregnancy-Induced; Pre-Eclampsia; Diabetes, Gestational; Drinking Water; Sweden; Alkanesulfonates; Fluorocarbons
PubMed: 37805182
DOI: 10.1016/j.envres.2023.117316 -
Drug Development Research Jun 2021An artificial series of macrocycles based on 4,4'-sulfonyldiphenol intermediate was synthesized using a multistep procedure involving oxidation of bisphenol sulfide,...
An artificial series of macrocycles based on 4,4'-sulfonyldiphenol intermediate was synthesized using a multistep procedure involving oxidation of bisphenol sulfide, etherification of phenolic hydroxyl groups, and final ring closure with different diamines. Different chemical species having aromatic, heteroaromatic, and aliphatic characters were incorporated into macrocyclic frameworks in the final step of ring closure. This simple and easily executable synthetic strategy was applied to synthesize 15 macrocycles (5a-o) in excellent yields. Characterization of the synthesized products was achieved through well-known modern spectroscopic techniques such as IR, NMR, and Mass. Macrocycles 5m and 5n were found to show significant AChE inhibition with IC values of 76.9 ± 0.24 and 71.2 ± 0.77 μM, respectively. Macrocycle 5n was also found to be an active inhibitor of butyrylcholinesterase (BChE) with IC score of 55.3 ± 0.54 μM. Among others, macrocycle 5l cyclized with o-phenylenediamine demonstrated moderate inhibition with IC value of 81.1 ± 0.54 μM. Increasing interest in studying interactions of macrocycles with different enzymatic targets compelled us to design and synthesize sulfone-based macrocycles that might prove as highly potent class of biologically active compounds.
Topics: Alzheimer Disease; Cholinesterase Inhibitors; Macrocyclic Compounds; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship; Sulfones
PubMed: 33368483
DOI: 10.1002/ddr.21775 -
Bioorganic Chemistry Nov 2022As the vital component of innate immune system, the NLRP3 inflammasome is implicated in the onset and progression of a variety of inflammatory diseases and has emerged...
As the vital component of innate immune system, the NLRP3 inflammasome is implicated in the onset and progression of a variety of inflammatory diseases and has emerged as an attractive drug target. Herein a series of novel phenyl vinyl sulfone based NLRP3 inflammasome inhibitors were designed, synthesized and biologically characterized. The most potent two hits 7a and 5b showed inhibition on the NLRP3 inflammasome with the IC of 1.83 ± 0.28 µM and 0.91 ± 0.06 µM, respectively. Further characterization confirmed their inhibition of NLRP3-mediated IL-1β release in vivo. Collectively, our findings encourage further research of more potent inhibitors based on this chemical scaffold.
Topics: Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Sulfones
PubMed: 35914391
DOI: 10.1016/j.bioorg.2022.106010