Specific Chelator Research Articles

Polyvinyl Chloride (PVC)-Glycerol with Chitosan Addition for Antibacterial Blood Bag Application

Blood bag is a medical device that stokes and transports whole blood or blood components. The material that is often used for blood bag membranes is Polyvinyl Chloride (PVC), however the common problem that is bacterial contamination and that material have not antibacterial characteristic. Because of this matter, the aim of this reseach are a blood bag that has antibacterial function is needed and meet the ideal standard as bloodbag. Chitosan as a blood bag membrane material fabrication to get the antibacterial effect. Chitosan is chosen as a blood bag material fabrication to get the antibacterial effect. Chitosan has several specific biocompatibility properties, antibacterial, chelation, and biodegradability. This study used various Chitosan concentrations of 1.5%, 2%, 2.5%, and 3%, and Glycerol was added as a plasticizer. The composition of Chitosan: Glycerol is 1:1. Then, the mixture is added to the PVC solution in a ratio of 1:5 then poured into a petri dish. The results showed characterization that the biocomposite PVC-Glycerol with the addition of 3% concentration of chitosan was the best composition, the tensile strength test result of biocomposite is 21.20 MPa, the absence of membrane pores in the morphology of the blood bag, the hemolytic activity is 0.24%, and the inhibition zones of E. coli and S. aureus, respectively 11.66 mm and 12.66 mm in diameter. Based on the characterization results, the biocomposite PVC-Glycerol membrane with the addition of Chitosan has a very high potential as a candidate for blood bag membranes

Facile fabrication of naphthalene-functionalized magnetic nanoparticles for efficient extraction of polycyclic aromatic hydrocarbons from environmental water and fish samples

In this study, naphthalene-modified magnetic nanoparticles (Fe3O4@Nap) were simply prepared based on specific chelation interaction between phosphate groups and metal ions on Fe3O4 surface. The resultant Fe3O4@Nap were characterized by FTIR, BET, SEM, TEM, NAM, TGA, and VSM techniques. With Fe3O4@Nap as adsorbent, the polycyclic aromatic hydrocarbons (PAHs) were efficiently extracted by magnetic solid-phase extraction (MSPE) from environmental water and fish samples through the π-π interaction between modified naphthalene groups and PAHs, followed by their determination by GC–MS/MS. The key parameters influencing the extraction efficiency were investigated. Under the optimized conditions, the Fe3O4@Nap-based MSPE/GC-MS/MS method proposed in this paper was evaluated and applied for analyzing PAHs in environmental water and fish samples. And the proposed MSPE/GC-MS/MS method exhibited good linearities for water samples (in the range of 0.1–10 ng/mL, R2 >0.9945) and for fish samples (in the range of 1–100 ng/g, R2 > 0.9905). The limits of detection (LODs) for water and fish samples were 0.004–0.031 ng/mL and 0.07–0.28 ng/g, respectively. Additionally, this method exhibited desirable accuracy and precision. The PAH recovery values from water and fish samples ranged from 81.5% to 109.6% with inter- and intra-day relative standard deviations (RSDs) of less than 12.8%. The MSPE/GC-MS/MS method was successfully applied to the analysis of real environmental water and fish samples. Overall, the newly synthesized Fe3O4@Nap exhibited high sensitivity, specificity, reusability, repeatability, and it could efficiently extract PAHs from environmental water and fish samples by MSPE.

A novel method of rapid detection for heavy metal copper ion via a specific copper chelator bathocuproinedisulfonic acid disodium salt

The extensive usage and production of copper may lead to toxic effects in organisms due to its accumulation in the environment. Traditional methods for copper detection are time consuming and infeasible for field usage. It is necessary to discover a real-time, rapid and economical method for detecting copper to ensure human health and environmental safety. Here we developed a colorimetric paper strip method and optimized spectrum method for rapid detection of copper ion based on the specific copper chelator bathocuproinedisulfonic acid disodium salt (BCS). Both biological assays and chemical methods verified the specificity of BCS for copper. The optimized reaction conditions were 50 mM Tris–HCl pH 7.4, 200 µM BCS, 1 mM ascorbate and less than 50 µM copper. The detection limit of the copper paper strip test was 0.5 mg/L by direct visual observation and the detection time was less than 1 min. The detection results of grape, peach, apple, spinach and cabbage by the optimized spectrum method were 0.91 μg/g, 0.87 μg/g, 0.19 μg/g, 1.37 μg/g and 0.39 μg/g, respectively. The paper strip assays showed that the copper contents of grape, peach, apple, spinach and cabbage were 0.8 mg/L, 0.9 mg/L, 0.2 mg/L, 1.3 mg/L and 0.5 mg/L, respectively. These results correlated well with those determined by inductively coupled plasma-mass spectrometry (ICP-MS). The visual detection limit of the paper strip based on Cu-BCS-AgNPs was 0.06 mg/L. Our study demonstrates the potential for on-site, rapid and cost-effective copper monitoring of foods and the environment.

Redox-active conjugated microporous polymer with favourable six-membered chelate ring for enhanced uranium extraction from highly acidic environments

Achieving extraction of strategic nuclide uranium with robust conjugated microporous polymers (CMPs) from highly acidic radioactive wastewater holds significant promise but is extremely challenging, as it needs powerful adsorbents with high selectivity, high capacity, and excellent stability. Herein, a redox-active conjugated microporous polymer (DHBA-HAH) with favourable six-membered chelate ring is innovatively reported by integrating hexaaminobenzene trihydrochloride (HAH) and 2,5-dihydroxy-1,4-benzenedicarboxaldehyde (DHBA). The unique structure of DHBA-HAH has all the features of being well tailored as a promising adsorbent for synergistic specific ligand chelation and efficient redox mineralization, and thus exhibits high uranium extraction capacity even under highly acidic conditions (0.59 mmol g−1, pH 2.0). Both experimental results and theoretical calculations confirm that the efficient extraction of uranium onto DHBA-HAH is a synergistic process of chemisorption and reduction, and both imidazole and hydroxyl functional groups play a decisive role in seizing uranium by forming a favorable six-membered chelate ring. This work presents a promising approach for the construction of high-performance uranium adsorbents with redox activity and opens up new pathways for the application of functionalized CMPs in eliminating radioactive contamination from strongly acidic environments.

A Paclitaxel Prodrug with Copper Depletion for Combined Therapy toward Triple-Negative Breast Cancer.

Tuning the content of copper is of great significance for the treatment of cancer and neurodegenerative diseases. Herein, we synthesized a redox-responsive paclitaxel (PTX) prodrug by conjugating PTX with a copper chelator through a disulfide bond. The as-fabricated prodrug (PSPA) showed specific chelation toward copper ions and could assemble with distearoyl phosphoethanolamine-PEG2000 to form stable nanoparticles (PSPA NPs) in aqueous media. Upon being internalized by tumor cells, PSPA NPs could respond to high levels of redox-active species inside cells and efficiently release PTX. The copper chelator could increase oxidative stress- and abnormal metabolism-induced cell death through intracellular copper depletion. The combination of chemotherapy and copper depletion therapy generated an enhanced therapeutic outcome toward triple-negative breast cancer with an ignorable systemic toxicity. Our work may provide insight into the combination of metabolic regulation and chemotherapy for combating malignant tumors.

Role of TPEN in Amyloid-β25-35-Induced Neuronal Damage Correlating with Recovery of Intracellular Zn2+ and Intracellular Ca2+ Overloading.

The overproduction of neurotoxic amyloid-β (Aβ) peptides in the brain is a hallmark of Alzheimer's disease (AD). To determine the role of intracellular zinc ion (iZn2+) dysregulation in mediating Aβ-related neurotoxicity, this study aimed to investigate whether N, N, N', N'‑tetrakis (2‑pyridylmethyl) ethylenediamine (TPEN), a Zn2+‑specific chelator, could attenuate Aβ25-35‑induced neurotoxicity and the underlying mechanism. We used the 3-(4, 5-dimethyl-thiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay to measure the viability of primary hippocampal neurons. We also determined intracellular Zn2+ and Ca2+ concentrations, mitochondrial and lysosomal functions, and intracellular reactive oxygen species (ROS) content in hippocampal neurons using live-cell confocal imaging. We detected L-type voltage-gated calcium channel currents (L-ICa) in hippocampal neurons using the whole‑cell patch‑clamp technique. Furthermore, we measured the mRNA expression levels of proteins related to the iZn2+ buffer system (ZnT-3, MT-3) and voltage-gated calcium channels (Cav1.2, Cav1.3) in hippocampal neurons using RT-PCR. The results showed that TPEN attenuated Aβ25-35‑induced neuronal death, relieved the Aβ25-35‑induced increase in intracellular Zn2+ and Ca2+ concentrations; reversed the Aβ25-35‑induced increase in ROS content, the Aβ25-35‑induced increase in the L-ICa peak amplitude at different membrane potentials, the Aβ25-35‑induced the dysfunction of the mitochondria and lysosomes, and the Aβ25-35‑induced decrease in ZnT-3 and MT-3 mRNA expressions; and increased the Cav1.2 mRNA expression in the hippocampal neurons. These results suggest that TPEN, the Zn2+-specific chelator, attenuated Aβ25-35‑induced neuronal damage, correlating with the recovery of intracellular Zn2+ and modulation of abnormal Ca2+-related signaling pathways.

Abstract 4901: The role of protein disulfide isomerase and copper in the paraptotic cell death of clinically investigated anticancer thiosemicarbazones

Abstract α-N-Heterocyclic thiosemicarbazones (TSCs) have long been investigated as anticancer compounds. Triapine is one of the best-known TSCs for anticancer therapy and is currently tested in a clinical phase III trial. To further improve the anticancer activity of TSCs, novel derivatives (such as DpC and COTI-2) have been developed and clinically investigated for their activity against solid tumors. These novel TSCs belong to a subclass (incl. the tetra-methylated Triapine derivative, Me2NNMe2) that are terminally disubstituted and demonstrated enhanced anticancer activity in vitro and in vivo. The improved activity of these TSCs correlated with their ability to form stable copper complexes as well as induce paraptosis, a form of programmed but caspase-independent cell death, that is characterized by the formation of vesicles originating from the endoplasmic reticulum (ER). However, the molecular events behind paraptosis induction are still not fully elucidated. Consequently, the aim of this study was to investigate the molecular signaling behind paraptosis as well as the reasons behind the induction of this quite unknown form of cell death by TSCs. A whole-genome gene expression analysis of cells treated with a terminally disubstituted TSC revealed an upregulation of thiol homeostasis-related genes, copper metabolism, and metallothionein genes as well as ER stress response genes. In addition, we found an upregulation of the copper-sensitive and thiol-containing protein disulfide isomerase (PDI), which was confirmed on protein level. In cell-free activity studies, PDI was indeed inhibited by terminally disubstituted TSCs, although only in form of their copper complexes. In agreement, removal of copper ions by specific chelators greatly reduced their anticancer activity as well as paraptotic potential in cell culture. This inhibition was hypothesized to be induced by a general disruption of the thiol redox homeostasis affecting also other responsive proteins and resulting in a more oxidative environment, especially in the ER. In confirmation, thiol-containing small molecules could reduce the compound’s anticancer activity in viability assays. Furthermore, glutathione as well as PDI were detected predominantly in their oxidized form in cells treated with terminally disubstituted TSCs. Consequently, terminally disubstituted TSCs, which are characterized by higher anticancer activity, induce paraptosis due to their high copper complex stability. The formation of the complex results in the interaction with thiol-containing proteins and subsequently in the disruption of the thiol-redox homeostasis, which leads to paraptotic cell death. Overall this work shed light on the paraptotic cell death and will be of interest for future clinical development of anticancer TSCs, as paraptosis is hypothesized to overcome apoptosis-resistance of cancer cells. Citation Format: Sonja Hager, Walter Berger, Christian R. Kowol, Eva A. Enyedy, Petra Heffeter. The role of protein disulfide isomerase and copper in the paraptotic cell death of clinically investigated anticancer thiosemicarbazones. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4901.

Abstract 5049: Pb-203 image guided Pb-212 receptor targeted alpha particle therapy for cancer - a powerful emerging paradigm

Abstract Objective: Pb-203 and Pb-212 have emerged as a promising elementally-matched theranostic pair for imaging-guided alpha-particle radiotherapy for cancer. A somatostatin receptor 2 (SSTR2)-targeted peptide coupled with novel Pb specific chelator (PSC) has been developed (PSC-PEG2-TOC). Here, preclinical in vitro and in vivo evaluation of 203Pb/212Pb-labeled PSC-PEG2-TOC was conducted including head to head therapy of SSTR2+ tumors in mice vs standard of care beta particle therapy and first in humans clinical imaging of SSTR2+ tumors. Method: [203Pb]PSC-PEG2-TOC and [212Pb]PSC-PEG2-TOC was prepared by published methods. Radiochemical stability of [203Pb]PSC-PEG2-TOC, [212Pb]PSC-PEG2-TOC and [212Bi]PSC-PEG2-TOC in human serum was determined. Binding affinity of [203Pb]PSC-PEG2-TOC was determined by binding assays in AR42J cells. In vivo SSTR2-mediated tumor targeting of [203Pb]PSC-PEG2-TOC was determined by SPECT imaging in athymic nude mice bearing AR42J xenografts. In vivo biodistribution of [212Pb]PSC-PEG2-TOC in normal organs and potential redistribution of 212Bi daughter were determined in CD-1 Elite mice. Clinical imaging was conducted under appropriate regulations to determine the biodistribution of the agent in patients bearing SSTR2+ tumors as determined by gold standard 68Ga-DOTATOC PET imaging. Results: Rapid incorporation of 203Pb and 212Pb in PSC-PEG2-TOC was observed after reactions at temperatures as low as 4°C within 15 min. Greater than 95% radiochemical stability was observed for both [203Pb]PSC-PEG2-TOC and [212Pb]PSC-PEG2-TOC after incubation in human serum for up to 55 hours. Stable decay product [212Bi]PSC-PEG2-TOC with minimal free 212Bi was observed. Agents demonstrated superior binding affinity to SSTR2 with Kd=0.59 nM. In in vivo studies, rapid tumor uptake and renal clearance of [203Pb]PSC-PEG2-TOC were observed in athymic nude mice bearing AR42J xenografts. In the biodistribution study, nearly identical biodistribution profiles of [212Pb]PSC-PEG2-TOC and progeny [212Bi]PSC-PEG2-TOC were found. No redistribution of 212Bi activity was identified, indicating that 212Bi remained co-localized with parent [212Pb]PSC-PEG2-TOC in vivo. Therapeutic studies in this same mouse model resulted in 100% complete responses for both a single dose 4.4 MBq administration of [212Pb]PSC-PEG2-TOC or a fractionated regimen of 4 × 1.1 MBq. First in humans clinical imaging showed PK properties that included rapid tumor accumulation and retention at over 20 h post administration, coupled with fast renal clearance of residual agent. Conclusion: [203Pb]PSC-PEG2-TOC and [212Pb]PSC-PEG2-TOC have promising potential for image-guide alpha-particle therapy for SSTR2 positive tumors. Agents have received a Fastrack designation by the US FDA and a safe to proceed for a Phase 1 trial. Citation Format: Michael King Schultz, Yusuf Menda, Dijie Liu, Mengshi Li, Frances Johnson, Brianna Cagle, Nicholas Baumhover, Ivy Vance. Pb-203 image guided Pb-212 receptor targeted alpha particle therapy for cancer - a powerful emerging paradigm. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5049.

Oxidation of TDMQ20, a Specific Copper Chelator as Potential Drug Against Alzheimer's Disease

AbstractDeveloped as a regulator of copper homeostasis in the brain of patients affected by Alzheimer's disease (AD), TDMQ20 is a specific copper(II) chelator able to restore short term memory in AD mice. To anticipate on metabolic studies of this drug‐candidate, here we report the catalytic oxidation of TDMQ20 by a biomimetic system reminiscent of P450 oxidation, using a metalloporphyrin and hydrogen persulfate as oxidant. Oxidation products were mainly characterized by HPLC with UV‐visible spectrometry or high‐resolution mass spectrometry detection. In these conditions, TDMQ20 was readily oxidized by aromatic hydroxylation, oxidation of 1,4‐diphenol or 1,4‐aminophenol to 1,4‐quinone or quinone‐imine, respectively, or oxidative chlorination. These putative metabolites were water‐soluble, suggesting that the drug‐candidate might be easily metabolized and excreted in vivo.

Preclinical Evaluation of a Lead Specific Chelator (PSC) Conjugated to Radiopeptides for 203Pb and 212Pb-Based Theranostics.

203Pb and 212Pb have emerged as promising theranostic isotopes for image-guided α-particle radionuclide therapy for cancers. Here, we report a cyclen-based Pb specific chelator (PSC) that is conjugated to tyr3-octreotide via a PEG2 linker (PSC-PEG-T) targeting somatostatin receptor subtype 2 (SSTR2). PSC-PEG-T could be labeled efficiently to purified 212Pb at 25 °C and also to 212Bi at 80 °C. Efficient radiolabeling of mixed 212Pb and 212Bi in PSC-PEG-T was also observed at 80 °C. Post radiolabeling, stable Pb(II) and Bi(III) radiometal complexes in saline were observed after incubating [203Pb]Pb-PSC-PEG-T for 72 h and [212Bi]Bi-PSC-PEG-T for 5 h. Stable [212Pb]Pb-PSC-PEG-T and progeny [212Bi]Bi-PSC-PEG-T were identified after storage in saline for 24 h. In serum, stable radiometal/radiopeptide were observed after incubating [203Pb]Pb-PSC-PEG-T for 55 h and [212Pb]Pb-PSC-PEG-T for 24 h. In vivo biodistribution of [212Pb]Pb-PSC-PEG-T in tumor-free CD-1 Elite mice and athymic mice bearing AR42J xenografts revealed rapid tumor accumulation, excellent tumor retention and fast renal clearance of both 212Pb and 212Bi, with no in vivo redistribution of progeny 212Bi. Single-photon emission computed tomography (SPECT) imaging of [203Pb]Pb-PSC-PEG-T and [212Pb]Pb-PSC-PEG-T in mice also demonstrated comparable accumulation in AR42J xenografts and renal clearance, confirming the theranostic potential of the elementally identical 203Pb/212Pb radionuclide pair.

Comparative Study of a Decadentate Acyclic Chelate, HOPO-O10, and Its Octadentate Analogue, HOPO-O8, for Radiopharmaceutical Applications.

Radiolanthanides and actinides are aptly suited for the diagnosis and treatment of cancer via nuclear medicine because they possess unique chemical and physical properties (e.g., radioactive decay emissions). These rare radiometals have recently shown the potential to selectively deliver a radiation payload to cancer cells. However, their clinical success is highly dependent on finding a suitable ligand for stable chelation and conjugation to a disease-targeting vector. Currently, the commercially available chelates exploited in the radiopharmaceutical design do not fulfill all of the requirements for nuclear medicine applications, and there is a need to further explore their chemistry to rationally design highly specific chelates. Herein, we describe the rational design and chemical development of a novel decadentate acyclic chelate containing five 1,2-hydroxypyridinones, 3,4,3,3-(LI-1,2-HOPO), referred to herein as HOPO-O10, based on the well-known octadentate ligand 3,4,3-(LI-1,2-HOPO), referred to herein as HOPO-O8, a highly efficient chelator for 89Zr[Zr4+]. Analysis by 1H NMR spectroscopy and mass spectrometry of the La3+ and Tb3+ complexes revealed that HOPO-O10 forms bimetallic complexes compared to HOPO-O8, which only forms monometallic species. The radiolabeling properties of both chelates were screened with [135La]La3+, [155/161Tb]Tb3+, [225Ac]Ac3+ and, [227Th]Th4+. Comparable high specific activity was observed for the [155/161Tb]Tb3+ complexes, outperforming the gold-standard 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, yet HOPO-O10 surpassed HOPO-O8 with higher [227Th]Th4+ affinity and improved complex stability in a human serum challenge assay. A comprehensive analysis of the decadentate and octadentate chelates was performed with density functional theory for the La3+, Ac3+, Eu3+, Tb3+, Lu3+, and Th4+ complexes. The computational simulations demonstrated the enhanced stability of Th4+-HOPO-O10 over Th4+-HOPO-O8. This investigation reveals the potential of HOPO-O10 for the stable chelation of large tetravalent radioactinides for nuclear medicine applications and provides insight for further chelate development.

S,N-rich luminous covalent organic frameworks for Hg2+ detection and removal

The challenge for simultaneous detection and removal of Hg2+ is the design of bifunctional materials bearing abundant accessible chelating sites with high affinity. Covalent-organic frameworks (COFs) are attracting more and more attention as potential bifunctional materials for Hg2+ detection due to their large specific surface area, ordered pores, and abundant chelating sites. Here, a new luminous S,N-rich COFBTT-AMPD based on hydrophilic block unit of 2,2′-azobis(2-methylpropionamidine) dihydrochloride (AMPD) was constructed, which improved the solubility and affinity for Hg2+ greatly. Another S-rich fused-ring unit of benzotrithiophene tricarbalaldehyde (BTT) enhanced the conjugation of COFBTT-AMPD, and the methyl-rich chains block unit of AMPD effectively suppressed the aggregation-caused quenching. Thus, the COFBTT-AMPD emitted strong fluorescence at 546 nm in liquid and solid as well as different solvent with a wide pH range, which was used for the visual detection and removal of Hg2+ (detection limit: 2.6 nM, linear range: 8.6 × 10−3-20 μM, monolayer adsorption capacity: 476.19 mg g−1) successfully. COFBTT-AMPD-based fabric and light-emitting diode coatings were further constructed to realize the visual detection of Hg2+ vapor. The results reveal the potential of S,N-rich luminous COFBTT-AMPD for Hg2+ detection and remediation in the environment.

Proteomics Evidence of the Role of TDMQ20 in the Cholinergic System and Synaptic Transmission in a Mouse Model of Alzheimer's Disease.

The interaction between copper ions and amyloid peptide Aβ has been reported to be involved in Alzheimer's disease (AD) pathology. Based on copper coordination biochemistry, we designed specific copper chelators [tetradentate monoquinolines (TDMQs)] in order to regulate copper homeostasis in the AD brain and inhibit the deleterious oxidative stress catalyzed by copper-Aβ complexes. We previously reported that TDMQ20, a highly selective copper chelator selected as a drug candidate, was able to extract copper from the Cu-Aβ1-16 complex and restore cognitive and behavioral deficits in AD mouse models. For a better understanding of the mechanism of action of TDMQ20, we decided to investigate the change of profile of proteins expressed in 5xFAD mice after an oral treatment of TDMQ20 (dose = 10 mg/kg, once every two days for 3 months, in total 45 times). Clioquinol (CQ), a non-specific chelator, has been used as a comparator. Here, we report the proteomic alterations in the cortex of 5xFAD mice using iTRAQ (isobaric tags for relative and absolute quantification) proteomics technology. The results indicated that 178 differentially expressed proteins (DEPs) have been identified in the AD mouse group with respect to wild type (WT) animals (AD/WT). After treatment by TDMQ20, 35 DEPs were found common in AD/WT and TDMQ20/AD groups in an opposite change manner (up- or down-regulated, respectively). In addition, among the 35 DEPs mentioned above, 10 common target proteins have been identified in AD/WT, TDMQ20/AD, and CQ/AD groups, among which 3 target proteins were successfully validated by western blot analysis. In particular, the expression levels of ChAT and CHRM4 are significantly increased upon TDMQ20 treatment with respect to 5xFAD mice, while CQ did not significantly change the expression of these proteins. Our study suggests the involvement of the copper chelator TDMQ20 on the cholinergic system, a feature that may explain the improved cognitive and behavioral performance in AD mice upon oral treatment of TDMQ20.

Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators.

Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide (1) or hydrazone (2–6) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-b]pyrrole derivative 1 was a strong inhibitor of the TET1 protein (IC50 = 1.33 μM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-b]pyrroles 2–6, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative 1 exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson’s correlation coefficient of 0.92.

Chelating Rare-Earth Metals (Ln3+) and 225Ac3+ with the Dual-Size-Selective Macrocyclic Ligand Py2-Macrodipa.

Radioisotopes of metallic elements, or radiometals, are widely employed in both therapeutic and diagnostic nuclear medicine. For this application, chelators that efficiently bind the radiometal of interest and form a stable metal-ligand complex with it are required. Toward the development of new chelators for nuclear medicine, we recently reported a novel class of 18-membered macrocyclic chelators that is characterized by their ability to form stable complexes with both large and small rare-earth metals (Ln3+), a property referred to as dual size selectivity. A specific chelator in this class called py-macrodipa, which contains one pyridyl group within its macrocyclic core, was established as a promising candidate for 135La3+, 213Bi3+, and 44Sc3+ chelation. Building upon this prior work, here we report the synthesis and characterization of a new chelator called py2-macrodipa with two pyridyl units fused into the macrocyclic backbone. Its coordination chemistry with the Ln3+ series was investigated by NMR spectroscopy, X-ray crystallography, density functional theory (DFT) calculations, analytical titrations, and transchelation assays. These studies reveal that py2-macrodipa retains the expected dual size selectivity and possesses an enhanced thermodynamic affinity for all Ln3+ compared to py-macrodipa. By contrast, the kinetic stability of Ln3+ complexes with py2-macrodipa is only improved for the light, large Ln3+ ions. Based upon these observations, we further assessed the suitability of py2-macrodipa for use with 225Ac3+, a large radiometal with valuable properties for targeted α therapy. Radiolabeling and stability studies revealed py2-macrodipa to efficiently incorporate 225Ac3+ and to form a complex that is inert in human serum over 3 weeks. Although py2-macrodipa does not surpass the state-of-the-art chelator macropa for 225Ac3+ chelation, it does provide another effective 225Ac3+ chelator. These studies shed light on the fundamental coordination chemistry of the Ln3+ series and may inspire future chelator design efforts.

Improving in vivo Uranyl Removal Efficacy of a Nano‐Metal Organic Framework by Interior Functionalization with 3‐Hydroxy‐2‐pyridinone

Comprehensive SummaryThe environmental contamination of uranium will occur in scenarios such as nuclear accidents and leakage from nuclear waste storage sites, which eventually leads to the internal uranium exposure of people, causing consequential injuries of renal failure, osteosarcoma, etc. The development of uranyl specific chelating agents that could sequester uranium in vivo is in urgent need and is important for the safe and efficient development of nuclear industry. Metal organic frameworks (MOFs) already serve as efficient uranium depletion materials in solutions of a wide range of pH and ionic strength for nuclear fuel recycling, uranium extraction from seawater, as well as environmental decontamination. Herein, a chromium‐based nano‐metal organic framework (nano‐MOF) functionalized interiorly with 3,2‐HOPO ligands, MIL‐101‐HOPO, is rationally synthesized. In vitro adsorption experiments show that MIL‐101‐HOPO exhibits high adsorption selectivity and fast adsorption kinetics for uranyl. The results of in vivo uranyl decorporation assays reveal that MIL‐101‐HOPO with the decoration of HOPO ligands on the interior wall exhibits significantly increased uranyl removal ratio in kidneys comparing to the pristine nMOFs, and is more effective than the clinically used ZnNa3‐DTPA. All those results corroborate the interior functionalization of MOFs as an efficient strategy to develop promising uranyl decorporation agents.

Phytochemical analysis by UPLC-QTOF-MS/MS and evaluation of antioxidant and anti-inflammatory activities of the extract and fractions from flowers of Cochlospermum vitifolium

Cochlospermum vitifolium (pacotê) is a medicinal plant used for treatment of hypertension, hepatitis, jaundice, hyperglycemia and inflammatory disorders. This study aimed to identify compounds present in ethanolic extract (EtOH) and hexane (Hex), ethyl acetate (EtOAc) and methanol/water (MeOH) fractions from C. vitifolium flowers and evaluate the antioxidant and anti-inflammatory potential. The phenolic compounds were characterized by UPLC-QTOF-MS/MS and 22 compounds were identified. The antioxidants effect of EtOH, Hex, EtOAc and MeOH fraction were investigated through quantification of total phenolic, diphenylpicryl hydrazine reduction, total antioxidant capacity, iron and cooper-chelating, reducing power, superoxide and hydroxyl radical scavenging assays. The anti-inflammatory potential of EtOH and EtOAc fraction (intra-gastric gavage route, 50, 100 or 150 mg/kg) were assayed by carrageenan-induced paw edema and zymosan-induced air pouch models. The EtOH and EtOAc fraction revealed higher concentration of phenolic compounds and antioxidant action when compared with Hex and MeOH fractions. The extract and fractions showed specific copper chelating effect. The EtOH and EtOAc fraction demonstrated be effective reducing the edema in carrageenan-induced paw edema model. In zymosan-induced air pouch model, the extract and fraction were able to decrease the leukocytes cells, proteins total and cytokines (IL-1β and IL-6) levels. This is the first study that demonstrated the antioxidant and anti-inflammatory effect of EtOH and EtOAc fraction of C. vitifolium flowers, suggesting that its phenolic compounds are, at least in part, responsible for anti-inflammatory effects.

Impacts of Mn, Fe, and Oxidative Stressors on MnSOD Activation by AtMTM1 and AtMTM2 in Arabidopsis.

It has been reported that the mitochondrial carrier family proteins of AtMTM1 and AtMTM2 are necessary for manganese superoxide dismutase (MnSOD) activation in Arabidopsis, and are responsive to methyl viologen (MV)-induced oxidative stress. In this study, we showed that MnSOD activity was enhanced specifically by Mn treatments. By using AtMnSOD-overexpressing and AtMnSOD-knockdown mutant plants treated with the widely used oxidative stressors including MV, NaCl, H2O2, and tert-butyl hydroperoxide (t-BH), we revealed that Arabidopsis MnSOD was crucial for root-growth control and superoxide scavenging ability. In addition, it has been reported that E. coli MnSOD activity is inhibited by Fe and that MTM1-mutated yeast cells exhibit elevated Fe content and decreased MnSOD activity, which can be restored by the Fe2+-specific chelator, bathophenanthroline disulfonate (BPS). However, we showed that BPS inhibited MnSOD activity in AtMTM1 and AtMTM2 single- and double-mutant protoplasts, implying that altered Fe homeostasis affected MnSOD activation through AtMTM1 and AtMTM2. Notably, we used inductively coupled plasma-optical emission spectrometry (ICP-OES) analysis to reveal an abnormal Fe/Mn ratio in the roots and shoots of AtMTM1 and AtMTM2 mutants under MV stress, indicating the importance of AtMTM1 in roots and AtMTM2 in shoots for maintaining Fe/Mn balance.

Ca2+ participates in the regulation of microalgae triacylglycerol metabolism under heat stress

Microalgae are the largest CO2 fixer and O2 producer on the earth and occupy an increasingly important position in human life and production. Various environmental factors have a significant impact on the growth and metabolism of microalgae. As global warming intensifies, heat stress has become a crucial factor affecting the microalgae industry. However, till now, it has not been clear how microalgae sensed the temperature stress, transmitted stress signals and adjusted in intracellular metabolic pathways. In this study, the growth of microalgae Auxenochlorella protothecoides UTEX2341 was inhibited at 32 °C, but the single cell dry weight increased. The cell component analyses showed that both the carbohydrate and total protein content decreased significantly, while the lipid content increased by 158%. Meanwhile, the intracellular Ca2+ concentration increased continuously, with a maximum increase of 1.65 times. According to the transcriptome analyses, the up-regulation of Ca2+ influx channel protein mid1-complementing activity 1 (MCA1) gene and the down-regulation of efflux channel protein cation exchanger 1(CAX) and autoinhibited Ca2+-ATPase 1 (ACA1) genes in cytoplasmic membrane jointly facilitated the increase of Ca2+ in the cytoplasm. Coexpression network analysis indicated that the fluctuation of Ca2+ in the cytoplasm could activate the expression of transcription factors MYB3 and AP2-4 through calmodulin (CAM) and calcium-dependent protein kinase (CDPK), and then regulate glycerol-3-phosphate acyltransferases (GPAT) at the beginning of TAG synthesis and diacylglycerol acyltransferase (DGAT)/phospholipid: diacylglycerol acyltransferase (PDAT) in the last step of TAG synthesis. Furthermore, the addition of Ca2+ specific chelator BAPTA-AM inhibited the expression of GPAT, which was consistent with the decrease in microalgae lipid content. The results proved that Ca2+ participated in the regulation of microalgae TAG synthesis under heat stress, which provided a new view for the understanding of the microalgae lipid accumulation mechanism.

Smartphone-based label-free photoelectrochemical sensing of cysteine with cadmium ion chelation.

As an important amino acid, cysteine is related to the development of various diseases. The quantitative detection of cysteine is of great significance for both disease diagnosis and treatment. The current labeling methods mainly rely on fluorescent probes, making it difficult for quantitative cysteine detection in point-of-care testing (POCT). In this study, we proposed a label-free method for cysteine quantification by novel photoelectrochemical (PEC) sensing using a specific ion chelation probe. An indium tin oxide electrode loaded with nanoscale graphitic carbon nitride (g-C3N4) was used as the PEC electrode and gold nanoparticle modification was performed to further promote the charge transfer efficiency for enhanced photocurrent detection. Cadmium ions (Cd2+) were employed as the specific ion chelation probe for cysteine detection, and the formed Cd2+/cysteine chelate complex served as the electron acceptor for sensitive PEC sensing under low-power LED illumination. A portable PEC system was developed for quantitative detection of cysteine by integrating the PEC sensor, a self-designed detection circuit and a smartphone. The detected photocurrents changed linearly with the cysteine concentrations ranging from 0 μM to 40 μM, and the limit of detection is calculated to be 9.2 μM. To demonstrate the capability of this system, cysteine in spiked urine samples was quantified with a recovery rate of 96.1%-100.57%. This system provides high portability, sufficient accuracy and sensitivity, and greatly reduces the complexity and cost of point-of-care cysteine detection.