Search

A high amount of iron in β-thalassemia patients can lead to oxidative stress and organ dysfunction, especially liver, the main iron accumulated organ. Iron catabolism causes the generation of reactive oxygen species (ROS), triggering liver inflammation, fibrosis, and cirrhosis. Deferiprone-resveratrol hybrid (DFP-RVT) is chemically synthesized by combining deferiprone (DFP) and resveratrol (RVT) which shows an iron-chelating property along with antioxidant activity. This study explored the hepatoprotective effect of DFP-RVT in iron overloaded β-knockout (BKO) thalassemic mice. The results revealed that DFP-RVT treatment improved liver function in iron-overloaded BKO mice by reducing liver enzymes and increasing hepcidin levels compared to iron overload control mice. Both DFP alone and DFP-RVT treatment groups demonstrated iron chelation effects by decreasing liver iron content (LIC), iron profiles, and iron deposition in the liver. Moreover, DFP-RVT powerfully showed antioxidant properties by decreasing liver and plasma thiobarbituric acid reactive substances (TBARs) and increasing reduced glutathione (GSH) and superoxide dismutase (SOD). Interestingly, transforming growth factor β1 (TGFβ1), which can contribute to chronic liver disease through liver injury, inflammation, fibrosis, and cirrhosis, is highly expressed in iron-overloaded mice. However, both DFP and DFP-RVT treatment significantly reduced TGFβ1 levels compared to the iron-overloaded group. Therefore, DFP-RVT could be a potent hepatoprotective compound through the mobilization of iron, reduction of ROS, improvement of liver enzymes, and alleviation of liver damage, potentially relieving liver dysfunction in iron-overloaded BKO mice., Competing Interests: Declaration of Competing Interest We wish to confirm that there are no known conflicts of interest associated with this manuscript and there has been no significant financial support for this work that could have influenced its outcome, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

An unprecedented eco-friendly multi-component domino reaction for the synthesis of novel N , O -acetals is reported. The protocol involves sequential coupling, [1,5]-hydride transfer and hetero-Diels-Alder cyclization. This new strategy enables direct α,β-difunctionalization of cyclic amines utilizing enamines generated in situ . The methodology features high atom and step economy, excellent regioselectivity, a simple work-up procedure and molecular diversity.

Herein, we describe an unprecedented Lewis acid-catalyzed annulation of phenols with o -aminobenzaldehydes via a cascade coupling/1,5-hydride transfer/cyclization sequence. The α- and β-positions of cyclic amines were functionalized utilizing enamines generated in situ . A series of complex N , O -acetal derivatives are synthesized in moderate to good yields in one step. The methodology features high atom and step economy, excellent diastereoselectivity, and water as the sole byproduct.

An organophotoelectrocatalytic method for the C(sp 2 )-H alkylation of heteroarenes with unactivated C(sp 3 )-H compounds through dehydrogenation cross-coupling has been developed. The C(sp 2 )-H alkylation combines organic catalysis, photochemistry and electrochemistry, avoiding the need for external metal-reagents, HAT-reagents, and oxidants. This protocol exhibits good substrate tolerance and functional group compatibility, providing a straightforward and powerful pathway to access a variety of alkylated heteroarenes under green conditions.

This work demonstrates the synthesis of a variety of perfluoroalkyl heterocycles via a visible-light-driven radical-polar crossover cyclization strategy. In this process, single-electron reduction/S N V-type/cyclization sequences follow the radical addition reaction of a diazoester, which differs from the current role of diazoesters as radical precursors/acceptors. This transformation demonstrates excellent functional group compatibility and allows for the modification of many bioactive molecules with diazoesters. Such a reaction could represent a novel approach to the photochemical transformation of diazo compounds.

Chronic liver diseases are complications of thalassemia with iron overload. Iron chelators are required to remove excessive iron, and antioxidants are supplemented to diminish harmful reactive oxygen species (ROS), purposing to ameliorate oxidative liver damage and dysfunctions. The deferiprone-resveratrol hybrid (DFP-RVT) is a synthetic iron chelator possessing anti-β-amyloid peptide aggregation, anti-malarial activity, and hepatoprotection in plasmodium-infected mice. The study focuses on investigating the antioxidant, cytotoxicity, iron-chelating, anti-lipid peroxidation, and antioxidant defense properties of DFP-RVT in iron-loaded human hepatocellular carcinoma (Huh7) cells. In the findings, DFP-RVT dose dependently bound Fe(II) and Fe(III) and exerted stronger ABTS • - and DPPH • -scavenging (IC 50 = 8.0 and 164 μM, respectively) and anti-RBC hemolytic activities (IC 50 = 640 μM) than DFP but weaker than RVT ( p < 0.01). DFP-RVT was neither toxic to Huh7 cells nor PBMCs. In addition, DFP-RVT diminished the level of redox-active iron ( p < 0.01) and decreased the non-heme iron content ( p < 0.01) in iron-loaded Huh7 cells effectively when compared without treatment in the order of DFP-RVT > RVT ∼ DFP treatments (50 µM each). Moreover, the compound decreased levels of hepatic ROS in a dose-dependent manner and the level of malondialdehyde, which was stronger than DFP but weaker than RVT. Furthermore, DFP-RVT restored the decrease in the GSH content and GPX and SOD activities ( p < 0.01) in iron-loaded Huh7 cells in the dose-dependent manner, consistently in the order of RVT > DFP-RVT > DFP. Thus, the DFP-RVT hybrid possesses potent iron chelation, antioxidation, anti-lipid peroxidation, and antioxidant defense against oxidative liver damage under iron overload., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Koonyosying, Korsieporn, Paradee, Hutachok, Xu, Ma, Chuljerm and Srichairatanakool.)

Printable mesoscopic perovskite solar cells (p-MPSCs) do not require the added hole-transport layer needed in traditional p-n junctions but have also exhibited lower power conversion efficiencies of about 19%. We performed device simulation and carrier dynamics analysis to design a p-MPSC with mesoporous layers of semiconducting titanium dioxide, insulating zirconium dioxide, and conducting carbon infiltrated with perovskite that enabled three-dimensional injection of photoexcited electrons into titanium dioxide for collection at a transparent conductor layer. Holes underwent long-distance diffusion toward the carbon back electrode, and this carrier separation reduced recombination at the back contact. Nonradiative recombination at the bulk titanium dioxide/perovskite interface was reduced by ammonium phosphate modification. The resulting p-MPSCs achieved a power conversion efficiency of 22.2% and maintained 97% of their initial efficiency after 750 hours of maximum power point tracking at 55 ± 5°C.

A Brønsted acid/iodine co-mediated approach to construct dihydropyrazino[2,3- b ]indoles in 2-MeTHF as a green solvent at room temperature was established. A wide range of diversely substituted dihydropyrazino[2,3- b ]indoles (42 examples, 61-85% yields) were synthesized under mild conditions, even on a gram scale. This protocol features organocatalysts, an eco-friendly solvent, mild conditions, readily accessible substrates, broad substrate scope and simple work-up.

Herein, we describe an efficient transition-metal-free regioselective C 3 alkylation of indoles for the synthesis of bis(indolyl)methanes and 3-styryl indoles. Nitrobenzene is employed as the oxidant to oxidize the alcohols in the presence of a strong base and the reaction avoids the use of transition metals such as Ru and Mn. The protocol provides a favorable route to access biologically active compounds such as arundine, vibrindole A, and turbomycin B.

Reactions with diverse C1 synthons to realize homologation were well explored. However, homologations occurring twice with one C1 synthon in a reaction were less reported. We disclose herein a Cu(II)-catalyzed novel and efficient synthesis of 2 H -chromenes from 2-naphthols, 1,3-diketones, and N , N -dimethylethanolamine (DMEA) as a dual carbon synthon. Various 2 H -chromenes with different functional groups are constructed in moderate to good yields. This is the first report that DMEA acts as a dual C1 synthon.

The chemical nature of intracellular labile iron pools (LIPs) is described. By virtue of the kinetic lability of these pools, it is suggested that the isolation of such species by chromatography methods will not be possible, but rather mass spectrometric techniques should be adopted. Iron-sensitive fluorescent probes, which have been developed for the detection and quantification of LIP, are described, including those specifically designed to monitor cytosolic, mitochondrial, and lysosomal LIPs. The potential of near-infrared (NIR) probes for in vivo monitoring of LIP is discussed.

We disclose herein an efficient photochemical formal [3+2+1] annulation strategy for the transformation of diazocarbonyl compounds into various fluorinated nitrogen-containing heterocycles. This transformation is characterized by reacting fluoroalkyl radicals with α-diazoketones, which are used as infrequent denitrogenated synthons under visible light. Moreover, a wide range of N-heterocycles containing precious CF 3 and perfluoroalkylated groups are constructed in moderate to good yields. Notably, this photochemical strategy may provide a fruitful path for the synthesis of complex organofluorides via diazo/fluorine/radical chemistry.

Herein, a Cu(II)-catalyzed facile construction of synthetically valuable spiro compounds from β-naphthols in air is reported, in which N , N -dimethylaminoethanol (DMEA) serves as an efficient and unique C1 synthon. This transformation proceeds through an ortho -quinone methide ( o -QM) formation/Michael addition/dearomatization sequence, affording various spiro(naphthalenenaphtho)furan-2-ones in moderate to excellent yields.

A palladium-catalyzed highly regioselective C-H allylation/annulation reaction of N -sulfonyl amides with secondary or tertiary allylic alcohols has been developed to construct 3,4-dihydroisoquinolones bearing a synthetically valuable vinyl substituent. This cascade cyclization approach of allylic alcohols involving C-H allylation has not been reported previously. The commercially available allylic alcohol substrates, the only by-product of water, and the used terminal oxidant of O 2 provide environmentally benign advantages.

Herein, we report a novel, rapid and efficient route to the spiroquinazolinone framework via an umpolung strategy mediated by molecular iodine. A library of functionalized spiroquinazolinone iodide salts was synthesized in moderate to good yields under ambient, metal-free and mild conditions. The current methodology opens up a new efficient and concise strategy for the construction of spiroquinazolinones.

Free heme in plasma acts as a prooxidant; thus, it is bound to hemopexin and eliminated by the liver. High iron content in the liver can support Plasmodium growth and cause oxidative liver injury. Inversely, the withholding of excessive iron can inhibit this growth and protect the liver against malaria infection. This study examined the effects of a deferiprone-resveratrol (DFP-RVT) hybrid on malaria parasites and its relevant hepatoprotective properties. Mice were infected with P. berghei , gavage DFP-RVT, deferiprone (DFP), and pyrimethamine (PYR) for 8 consecutive days. Blood and liver parameters were then evaluated. The presence of blood-stage parasites was determined using the microscopic Giemsa staining method. Subsequently, plasma liver enzymes, heme, and concentrations of thiobarbituric acid-reactive substances (TBARS) were determined. The liver tissue was examined pathologically and heme and TBARS concentrations were then quantified. The results indicate that the suppression potency against P. berghei growth occurred as follows: PYR > DFP-RVT hybrid > DFP. Importantly, DFP-RVT significantly improved RBC size, restored alanine aminotransferase and alkaline activities, and increased heme and TBARS concentrations. The compound also reduced the liver weight index, heme, and TBARS concentrations significantly when compared to mice that were untreated. Our findings support the contention that the hepatoprotective effect of DFP-RVT is associated with parasite burden, iron depletion, and lipid peroxidation in the host., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Hataichanok Chuljerm et al.)

An efficient I 2 -promoted one-pot one-step three-component reaction for the synthesis of sulfhydryl indolizines from methyl ketones, 2-pyridylacetate derivatives, and sulfonyl hydrazides via an in situ cyclization-rethiolation strategy has been developed. This protocol shows excellent substrate compatibility, including for chain and cyclic aliphatic methyl ketones, natural product pregnenolone acetate, and phosphorus-containing methyl ketones, affording a series of valuable aliphatic-substituted indolizines in good yields.

A facile synthetic protocol for the preparation of spiro diheterocycles from easily available 2'-aminoacetophenones, isocyanates and 1,4-benzoquinones or quinone monoimines under mild conditions has been developed. This multi-component transformation is characterized by efficient construction of two heterocycles and one valuable quaternary carbon in one pot via an in situ cyclization-respiroannulation strategy. Moreover, this reaction showed a broad substrate scope, and generated diverse five-membered oxaspiros.

The synthesis of N -heterocycles composes a significant part of synthetic chemistry. In this report, a Cu(II)-catalyzed green and efficient synthesis of pyrrolo[1,2- a ]quinoxaline, quinazolin-4-one, and benzo[4,5]imidazoquinazoline derivatives was developed, employing N,N -dimethylethanolamine (DMEA) as a C1 synthon. Green oxidant O 2 is critical in these transformations, facilitating the formation of a key intermediate─a reactive iminium ion. The method conducted under mild conditions is compatible with a diversity of functional groups, providing an appealing alternative to the previously developed protocols.

Herein, we reported a metal-free photoredox/phosphine-catalyzed C-H amination of arenes. This allows for concise synthesis of highly functionalized N -arylphthalimides from readily available N -hydroxyphthalimides directly, without the preparation of activated N -hydroxyphthalimide intermediates. Mechanistic studies reveal that the radical is produced via phosphine-mediated N-O bond scission.

A green and facile synthesis of previously unreported C , N -disulfonated 5-amino pyrazoles was established through an iodine-catalyzed cascade reaction of easily accessible sulfonyl hydrazides, β-ketonitriles, and sodium sulfinates. Diverse C , N -disulfonated 5-amino pyrazoles could be obtained in 38-88% yields. This methodology features green and mild conditions, broad substrate scope, and effortless work-up.

The multicomponent-multicatalyst reaction ((MC) 2 R) and visible-light catalysis have emerged as green and powerful strategies for achieving ideal syntheses. Here, we report the first example of a visible-light-induced approach toward spiroquinazolin(thi)ones. This (MC) 2 R features an eco-friendly energy source and solvent, metal-free catalysts, step- and atom-economy, a relay catalysis strategy, air as green oxidant, mild conditions, and easily accessible starting materials.

Background: Lung cancer is the primary cause of cancer-related mortality worldwide. The anticancer effect of stilbene has been noted in various tumor types. GMQ3, which has a stilbene-mimicking skeleton, is a novel small-molecule compound with promising antitumor activity. Our results revealed that GMQ3 not only suppressed cell proliferation and cell migration of lung cancer cells but also led to G1 phase cell cycle arrest and triggered caspase-dependent apoptosis. Furthermore, investigation of the molecular mechanism showed that GMQ3 could inhibited proliferation and induced apoptosis via the p38-MAPK/SIRT1 pathway both in vitro and in vivo. Xenograft tumor mouse models showed that GMQ3 significantly inhibited tumor growth in vivo without affecting body weight. Our findings indicated that GMQ3 exerts a strong anticancer action by suppressing cell proliferation, inhibiting cell migration and inducing cell apoptosis. Moreover, the efficacy of GMQ3 was enhanced in the presence of CDK4/6 inhibitor Abemaciclib. We conclude that GMQ3 is a promising agent with potential for lung cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

An efficient, facile, and eco-friendly synthesis of pyrimidine derivatives has been developed. It involves a [3 + 2 + 1] three-component annulation of amidines, ketones, and one carbon source. N , N -Dimethylaminoethanol is oxidized through C(sp 3 )-H activation to provide the carbon donor. One C-C and two C-N bonds are formed during the oxidative annulation process. The reaction shows good tolerance to many important functional groups in air, making this methodology a highly versatile alternative, and significant improvement to the existing methods for structuring a pyrimidine framework, especially 4-aliphatic pyrimidines.

Iron is essential for all organisms including fast-dividing malarial parasites. Inversely, iron chelators can inhibit parasite growth through the inhibition of DNA synthesis and can ameliorate oxidative cell damage. Deferiprone (DFP)-resveratrol (RVT) hybrid (DFP-RVT) is a lipophilic anti-oxidative, iron-chelating agent that has displayed potent neuroprotective and anti-plasmodium activities in vitro. The goal of this work was to investigate the inhibitory effects of DFP-RVT on parasite growth and oxidative stress levels during malaria infections. Mice were intraperitoneally infected with P. berghei and orally administered with DFP, DFP-RVT and pyrimethamine for 4 d. The percentage of parasitemia was determined using Giemsa's staining/microscopic examination. Amounts of the lipid-peroxidation product, thiobarbituric acid-reactive substance (TBARS), were determined in both plasma and liver tissue. In our findings, DFP-RVT exhibited a greater potent inhibitory effect and revealed an improvement in anemia and liver damage in infected mice than DFP. To this point, the anti-malarial activity was found to be associated with anti-RBC hemolysis and the liver weight index. In addition, plasma and liver TBARS levels in the DFP-RVT-treated mice were lower than those in DFP-treated mice. Thus, DFP-RVT could exert anti-plasmodium, anti-hemolysis and anti-lipid peroxidation activities to a better degree than DFP in P. berghei -infected mice.

We report an efficient iron-catalyzed cross-dehydrogenative coupling [4 + 2] annulation of secondary/tertiary anilines with quinazolinones to generate quinoline-spiroquinzolinones. The reaction proceeds smoothly with a relatively broad variety of functional groups, a cheap transition metal catalyst (FeCl 3 ), and environmentally friendly oxidant (H 2 O 2 /O 2 ) under mild reaction conditions. Creatively, N -methylanilines are employed for the first time for the cycloaddition as both methyl and methylene sources attached to the N atom of tetrahydroquinolines.

An efficient approach for the reversal of regioselectivity in the nucleophilic introduction of difluorinated carbanion into α,β-enones has been developed via a silylium catalysis. The strong electron-withdrawing properties and bulky substituents of in situ-generated silyl triflic imide catalyst is the key for the 1,4-addition reaction to proceed smoothly. The synthetic utility is highlighted by the further use of this method for the synthesis of 2,4,6-triarylsubstituted 3-fluoropyridines in a one-pot manner.

A transition metal-free method for de novo construction of diverse sulfonated pyrazoles from readily available sulfonyl hydrazides, 1,3-diketones, and sodium sulfinates was established under mild conditions. Pyrazoles bearing two different sulfonyl groups were obtained in one step. The method features a diversity of substituents of the pyrazole products and a remarkably simple work-up.

Malaria i a serious health problem caused by Plasmodium spp. that can be treated by an anti-folate pyrimethamine (PYR) drug. Deferiprone (DFP) is an oral iron chelator used for the treatment of iron overload and has been recognized for its potential anti-malarial activity. Deferiprone-resveratrol hybrids (DFP-RVT) have been synthesized to present therapeutic efficacy at a level which is superior to DFP. We have focused on determining the lipophilicity, toxicity and inhibitory effects on P. falciparum growth and the iron-chelating activity of labile iron pools (LIPs) by DFP-RVT. According to our findings, DFP-RVT was more lipophilic than DFP ( p < 0.05) and nontoxic to blood mononuclear cells. Potency for the inhibition of P. falciparum was PYR > DFP-RVT > DFP in the 3D7 strain (IC 50 = 0.05, 16.82 and 47.67 µM, respectively) and DFP-RVT > DFP > PYR in the K1 strain (IC 50 = 13.38, 42.02 and 105.61 µM, respectively). The combined treatment of DFP-RVT with PYR additionally enhanced the PYR activity in both strains. DFP-RVT dose-dependently lowered LIP levels in PRBCs and was observed to be more effective than DFP at equal concentrations. Thus, the DFP-RVT hybrid should be considered a candidate as an adjuvant anti-malarial drug through the deprivation of cellular iron.

A selective and efficient synthesis of diaryl 1,3,5-oxadiazines was established for the first time from simple and readily available amidines in wet DMSO. DMSO was employed as a dual carbon synthon and water offered the oxygen atom to construct the oxadiazine ring. The reaction involved two new C-N and two new C-O bond formations.

A convenient one-pot, three-component reaction has been developed for the synthesis of 3-aroylimidazo[1,2- a ]- N -heterocycles from aryl ketones and 2-amino- N -heterocycles using dimethyl sulfoxide as a methylene donor. The reaction proceeds smoothly catalyzed by I 2 in the presence of K 2 S 2 O 8 and affords the desired products in moderate to good yields. This protocol offers significant superiority in accessing biologically active 3-aroylimidazo[1,2- a ]- N -heterocycles with various substitution patterns.

Background: Allergic rhinitis (AR) is characterized by type I hypersensitivity that is mediated by IgE-induced humoral responses. Follicular helper T cells (Tfh) comprise the key helper T cell (Th) subset that promotes antibody production. Signaling lymphocytic activation molecules (SLAMs) participate in regulation of the differentiation and function of Tfh cells, but whether this regulation is involved in the pathogenesis of AR is unknown., Methods: CD4+CXCR5+ Tfh-like cells from peripheral blood were detected by flow cytometry. The IL-21 and IgE levels in serum were measured by an ELISA. Blood CD4+CXCR5+ Tfh-like cells were sorted and cultured with anti-SLAM mAb in vitro., Results: The frequencies of circulating CD4+CXCR5+ Tfh-like cells appeared virtually unchanged in AR patients, but the expression of SLAMs and SLAM-associated protein (SAP) on circulating Tfh-like cells was significantly decreased. Meanwhile, the level of serum IL-21 was increased in AR patients, and a negative correlation was found between the IL-21 level and SLAM or SAP expression on CD4+CXCR5+ T cells. Treatment with anti-SLAM mAb resulted in reduced IL-21 production by Tfh-like cells in vitro. Additionally, SLAM expression on B cells was significantly decreased, although the percentages of B cells were increased in AR patients., Conclusion: SLAMs negatively regulate IL-21 production in CD4+CXCR5+ Tfh-like cells, which contributes to the pathogenesis of AR., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Yang et al.)

A one-pot, four-component annulation of 2,3,4,6-tetraarylpyridines from aromatic aldehydes, methyl ketones, diaryl ethanones, and ammonium acetate is described. The reaction features high functional group compatibility in air under solvent-free conditions without any additive and only water as the nontoxic byproduct, providing a strategy for the facile, economical, and eco-friendly construction of multiaryl-substituted pyridines from simple and readily available reactants.

A novel procedure for a one-pot cascade reaction of o -aminoacetophenones and aryl/aliphatic isocyanates catalyzed/oxidized by the [Pd]/[Ag] system was developed. The reaction involves two C-N bond and one C-C bond formations during the double annulation process and the desired indoloquinazolinones and derivatives were afforded up to 81% yields from readily available substrates with a tolerance of a broad variety.

A simple and practical domino protocol for the selective synthesis of 2-aroylbenzothiazoles and 2-aryl benzothiazoles catalyzed by I 2 is developed under metal-free conditions. The reaction outcomes are exclusively controlled by the reaction oxidant/medium. With DMSO employed as both the solvent and the oxidant, an oxidation of aromatic methyl ketones takes precedence over the condensation with 2-aminobenzenethiols. On the other hand, when the reaction was carried out in PhNO 2 or in 1,4-dioxane containing PhNO 2 , the condensation of aromatic methyl ketones with 2-aminobenzenethiols has priority to form imines which is followed by an oxidation of the methyl group from ketones to afford 2-arylbenzothiazoles as a sole product. The PhNO 2 /I 2 co-catalytic system is proposed first time.

1,2-Dihydro-1,3,5-triazines and symmetrical 1,3,5-triazines were obtained in up to 81% yields from amidines and N,N-dimethylethanolamine catalyzed by CuCl2. The reaction involves three C-N bond formations during the oxidative annulation process and the mechanism was proposed. This efficient synthesis of 1,2-dihydro-1,3,5-triazines was developed for the first time.

A palladium-catalyzed tandem dehydrogenative [4 + 2] annulation of terminal olefins with N -sulfonyl amides via C(sp 2 )-H activation, allylic C(sp 3 )-H activation, and homoallylic C(sp 3 )-H elimination processes has been developed. Promoted by the DMSO ligand, various benzamides, heterocyclic arylamides, alkenyl carboxamides, and commercial olefins are found to be efficient substrates to construct important heterocyclic compounds bearing a vinyl substituent with high E stereoselectivity. Using air as the terminal oxidant also provides a great advantage regarding environmental friendliness.

A new series of 3-substituted 4-methylene-quinazolinthiones and 4-methylene-quinazolinones were synthesized in moderate to excellent yield through a simple reaction of 2-aminoacetophenones with isocyanates or isothiocyanates. The reaction shows good tolerance of many important functional groups in the presence of air and water under metal-free conditions. Only water is produced as a coproduct, rendering this "green" methodology a highly versatile and eco-friendly alternative to the existing methods for the construction of the quinazolinone/quinazolinthione framework. We have interpreted the reaction mechanism by use of quantum chemical calculations on the basis of state-of-the-art computational methods SMD-B3LYP-D3(BJ)/BS1//B3LYP/BS1.

An efficient method for the synthesis of 3-functionalized quinolines from commercially available acetophenones and anthranil has been described. Selectfluor propels the C(sp 3 )-H bond activation of the acetophenones and aza-Michael addition of anthranil resulting in annulated 3-acylquinolines in moderate to high yields. DMSO acts not only as a solvent but also as a one carbon donor in the reaction., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

We report a self-assembly-based approach for improved iron chelation of small chelators. A model chelator, deferiprone (DFP) is covalently linked to amphiphilic poly(ethylene glycol)-polypeptide block copolymer that can assemble into micelles. The free DFP generally coordinates with iron in a ratiometric manner (3:1). However, the assembly induces DFP packing in the micelle cores, which restricts its conformational freedom. Hence DFP/iron coordination ratio in micelles is reduced (< 3:1), which leads to an enhanced chelation performance of DFP. In addition, the micellar nanocarrier usually exhibits an extended systemic circulation in contrast to the free DFP. The current work opens new avenues for developing novel nanomedicines for iron overload diseases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The 3-hydroxypyran-4-one moiety (maltol) was incorporated into the structure of resveratrol to achieve a series of resveratrol-maltol hybrids (8a-8k) as novel multi-target-directed ligands (MTDLs). In vitro biological evaluation of the MTDLs revealed these compounds to have a triple function, namely inhibition of self-induced Aβ 1-42 aggregation, antioxidation, and metal chelating activity. Among all the evaluated MTDLs, compounds 8i and 8j showed the most promise, demonstrating micromolar IC 50 values for Aβ 1-42 aggregation inhibition, more potent ABTS + scavenging activity than Trolox, and good metal chelating activities., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Hydroxypyridinones (HOPOs) form outstanding building blocks for the development of a variety of agents in the field of metal chelation. The pyridinone ring is easily synthesized and readily converted into tetradentate, hexadentate, and octadentate chelators. There is considerable potential for the control of the stereochemistry of the resulting metal complex and hence the properties of these multidentate molecules. Their ability to rapidly bind hard metals in aqueous media has facilitated the development of efficient applications in both biological and medical contexts. In this Review, an in-depth analysis of the synthetic methodologies for HOPO-based ligands is presented, as well as the many aspects to achieve optimal biological activity. Recent advances and current challenges for the future application of HOPO structures are outlined. The present flourishing development of drug candidates and diagnostic agents based on this chemical scaffold opens access to many new applications in analytical, environmental, and clinical science.

A series of deferiprone-resveratrol hybrids have been designed and synthesized as multitarget-directed ligands (MTDLs) through merging the chelating moiety 3-hydroxypyridin-4-one into the structure of resveratrol, a natural antioxidant agent and β-amyloid peptide (Aβ) aggregation inhibitor. The in vitro biological evaluation revealed that most of these newly synthesized compounds exhibited good inhibitory activity against self-induced Aβ 1-42 aggregation, excellent antioxidant activity and potent metal chelating capability. Compounds 3i and 4f were identified as the most promising MTDLs with triple functions, possessing micromolar IC 50 values for Aβ 1-42 aggregation inhibition, greater 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS •+ ) scavenging activity than Trolox and similar pFe(III) values to that of deferiprone., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Nontransferrin-bound iron (NTBI) is a heterogeneously speciated plasma iron, typically detectable when transferrin saturation (TfSat) exceeds 75%. Here, we examine factors affecting NTBI levels by a recently discovered direct chelator-based (CP851) fluorescent bead-linked flow-cytometric assay (bead-NTBI), compared with the established indirect nitrilotriacetate (NTA) assay in 122 iron-overloaded patients, including 64 on recent iron chelation therapy and 13 healthy volunteers. Both methods correlated (r = 0.57, P < 0.0001) but with low agreement, attributable to 2 major factors: (1) the NTA method, unlike the bead method, is highly dependent on TfSat, with NTBI under-estimation at low TfSat and over-estimation once Tf is saturated, (2) the bead method detects <3-fold higher values than the NTA assay in patients on recent deferiprone-containing chelation due to greater detection of chelate complexes but lower values for patients on deferasirox. The optimal timing of sample collection relative to chelation dosing requires further study. Patients with splenectomy, high-storage iron, and increased erythropoiesis had greater discrepancy between assays, consistent with differential access by both methods to the NTBI pools associated with these clinical variables. The bead-NTBI assay has advantages over the NTA assay, being less dependent on TfSat, hence of less tendency for false-negative or false-positive values at low and high TfSat, respectively., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The fluorescence intensity of the iron-CP691 complex in the presence of a competing multidentate ligand is associated with pFe(3+) of the competing ligand and the relative fluorescence has a linear correlation with the pFe(3+) values. A correlation was also found to exist between the relative fluorescence and the ratio of a competing ligand to the probe CP691. Based on this assay, the pFe(3+) value of a range of hexadentate ligands, dendrimers and polymers can be determined when they fall in the range 24.5-30.5. Only small quantities of chelators are required for this assay.

A series of caudatin ester derivatives were synthesized and tested for their activities against human lung cancer A549, human prostate cancer PC3, human liver cancer BEL-7402 and human gastric cancer SGC-7901 cell lines. All the compounds showed noticeable activities against the tested tumor cell lines, and the IC50s are all lower than that of caudatin. Among them, 5e and 5h are the most potent compounds. SAR study implies that introducing either a halogenated acyl group or amino aryl group to the C3β position of caudatin is beneficial to their anti-viability activities, and the lipophilicity affects the anti-viability activity of caudatin derivatives.

Due to its long half-life (78 h) and decay properties (77% electron capture, 23% β(+), Emax = 897 keV, Eav = 397 keV, Eγ = 909 keV, Iγ = 100%) (89)Zr is an appealing radionuclide for immunoPET imaging with whole IgG antibodies. Derivatives of the siderophore desferrioxamine-B (H3DFO) are the most widely used bifunctional chelators for coordination of (89)Zr(4+) because the radiolabeling of the resulting immunoconjugates is rapid under mild conditions. (89)Zr-DFO complexes are reportedly stable in vitro but there is evidence that (89)Zr(4+) is released in vivo, and subsequently taken up by the skeleton. We have evaluated a novel tripodal tris(hydroxypyridinone) chelator, H3CP256 and its bifunctional maleimide derivative, H3YM103, for coordination of Zr(4+) and compared the NMR spectra, and the (89)Zr(4+) radiolabeling, antibody conjugation, serum stability and in vivo distribution of radiolabelled immunoconjugates with those of H3DFO and its analogues. H3CP256 coordinates (89)Zr(4+) at carrier-free concentrations forming [(89)Zr(CP256)](+). Both H3DFO and H3CP256 were efficiently radiolabelled using [(89)Zr(C2O4)4](4-) at ambient temperature in quantitative yield at pH 6-7 at millimolar concentrations of chelator. Competition experiments demonstrate that (89)Zr(4+) dissociates from [(89)Zr(DFO)](+) in the presence of one equivalent of H3CP256 (relative to H3DFO) at pH 6-7, resulting largely in [(89)Zr(CP256)](+). To assess the stability of H3DFO and H3YM103 immunoconjugates radiolabelled with (89)Zr, maleimide derivatives of the chelators were conjugated to the monoclonal antibody trastuzumab via reduced cysteine side chains. Both immunoconjugates were labelled with (89)Zr(4+) in >98% yield at high specific activities and the labeled immunoconjugates were stable in serum with respect to dissociation of the radiometal. In vivo studies in mice indicate that (89)Zr(4+) dissociates from YM103-trastuzumab with significant amounts of activity becoming associated with bones and joints (25.88 ± 0.58% ID g(-1) 7 days post-injection). In contrast, <8% ID g(-1) of (89)Zr activity becomes associated with bone in animals administered (89)Zr-DFO-trastuzumab over the course of 7 days. The tris(hydroxypyridinone) chelator, H3CP256, coordinates (89)Zr(4+) rapidly under mild conditions, but the (89)Zr-labelled immunoconjugate, (89)Zr-YM103-trastuzumab was observed to release appreciable amounts of (89)Zr(4+)in vivo, demonstrating inferior stability when compared with (89)Zr-DFO-trastuzumab. The significantly lower in vivo stability is likely to be a result of lower kinetic stability of the Zr(4+) tris(hydroxypyridinone complex) relative to that of DFO and its derivatives.

Several iron-sensitive fluorophores have been investigated in a range of cell types in order to quantify iron(II) levels in the cytosol and the cytoplasm. Both iron(II) and iron(III) cause fluorescence quenching of these probes and changes in cytosolic iron levels can be monitored in a reproducible manner. However the precise quantification of iron(II) in the cytosol is complicated by the uncertainty of the structure of many of the quenched species that exist under in vivo conditions. Precise knowledge of these structures is essential for quantitative purposes. The lysosomal and mitochondrial iron pools have only been the subject of relatively few studies at the time of writing. Calcein-AM has been widely adopted for the monitoring of changes in iron levels in a range different cell types.

Background: Deferiprone has proved to be a successful iron selective chelator in a range of pathologies. However, its use is limited by rapid Phase II metabolism, necessitating the administration of large doses. In an attempt to modify metabolic rate of this class of compounds, a range of pegylated 3-hydroxypyridin-4-ones has been synthesized., Experimental: The synthetic route in which the polyethylene glycol counterparts are introduced to a protected pyran ring involves either a Williamson etherification reaction or direct addition leading to polyethylene glycol-containing precursors., Results & Discussion: The introduction of the pegylated substituent was found to lead to a relatively low rate of metabolism for some of the derivatives (6a, 6b, 8a and 8b), offering a possible improvement over deferiprone.