Iron-chelating Agent Research Articles

Iron Chelation as a Potential Therapeutic Strategy for AKI Prevention.

AKI remains a major public health concern. Despite years of investigation, no intervention has been demonstrated to reliably prevent AKI in humans. Thus, development of novel therapeutic targets is urgently needed. An important role of iron in the pathophysiology of AKI has been recognized for over three decades. When present in excess and in nonphysiologic labile forms, iron is toxic to the kidneys and multiple other organs, whereas iron chelation is protective across a broad spectrum of insults. In humans, small studies have investigated iron chelation as a novel therapeutic strategy for prevention of AKI and extrarenal acute organ injury, and have demonstrated encouraging initial results. In this review, we examine the existing data on iron chelation for AKI prevention in both animal models and human studies. We discuss practical considerations for future clinical trials of AKI prevention using iron chelators, including selection of the ideal clinical setting, patient population, iron chelating agent, and dosing regimen. Finally, we compare the key differences among the currently available iron chelators, including pharmacokinetics, routes of administration, and adverse effects.

Catechol-Loading Nanofibrous Membranes for Eco-Friendly Iron Nutrition of Plants.

Modern agriculture requires more efficient and low-impact products and formulations than traditional agrochemicals to improve crop yields. Iron is a micronutrient essential for plant growth and photosynthesis, but it is mostly present in insoluble forms in ecosystems so that it is often limiting for plants. This study was aimed at combining natural strategies and biodegradable nanostructured materials to create environmentally friendly and low-toxic bioactive products capable of both supplying iron to Fe-deficient plants and reducing the impact of agricultural products on the environment. Consequently, free-standing electrospun nanofibrous polycaprolactone/polyhydroxybutyrate thin membranes loaded with catechol (CL-NMs) as an iron-chelating natural agent (at two concentrations) were fabricated on purpose to mobilize Fe from insoluble forms and transfer it to duckweed (Lemna minor L.) plants. The effectiveness of CL-NMs in providing iron to Fe-deficient plants, upon catechol release, tested in duckweeds grown for 4 days under controlled hydroponic conditions, displayed temporal variations in both photosynthetic efficiency and biometric parameters measured by chlorophyll fluorescence and growth imaging. Duckweeds supplied with CL-NMs hosting higher catechol concentrations recovered most of the physiological and growth performances previously impaired by Fe limitation. The absence of short-term toxicity of these materials on duckweeds also proved the low impact on ecosystems of these products.

Assessment of serum ferritin levels in transfusion dependent thalassemic children on oral deferiprone in a tertiary care centre

Background: Thalassemic patients require regular blood transfusions to maintain haemoglobin level around between 10gm/dl-15gm/dl, which would result in transfusional iron overload. The treatment of iron overload is carried out by using parenteral desferrioxamine (DFX) therapy or recently introduced oral Deferiprone (DFP,L1,Ferriprox,KELFER,CP20) an oral iron chelator, Oral deferiprone, DFP (3-hydroxy-1,2-dimethylpyridin-4-one) is a synthetic analogue of mimosine, an iron chelator isolated from the legume Mimosa paduca. Our study was undertaken to asses ferritin concentration in transfusion dependent thalassemic children on Deferiprone, attending thalassemia clinic in Anil Neerukonda hospital, Sanghivalasa, Visakhapatnam.Methods: The present study was a hospital based prospective study, 50 transfusion dependent thalassemic children on Deferiprone, attending thalassemia clinic in Anil Neerukonda hospital, Sanghivalasa, Visakhapatnam attached to NRI Medical College, Visakhapatnam were enrolled during the study period October 2017 and September 2018.Results: In our study authors found an increase in Serum ferritin concentration from 3067.99±1520.13 to 4281.10 ±1760.42 ng/ml at the end of 12 months, which was quite significant.Conclusion: Authors concluded that oral Deferiprone is not an effective iron chelation agent and is associated with complications like GI symptoms, joint pains in significant number of children. So, search for an alternative iron chelator or combined chelation therapies which are safe and cost effective should be continued.

An unexpected new pathway for nitroxide radical production via more reactve nitrogen-centered amidyl radical intermediate during detoxification of the carcinogenic halogenated quinones by N-alkyl hydroxamic acids

We found previously that nitroxide radical of desferrioxamine (DFO•) could be produced from the interaction between the classic iron chelating agent desferrioxamine (DFO, an N-alkyl trihydroxamic acid) and tetrachlorohydroquinone (TCHQ), one of the carconogenic quinoind metabolites of the widely used wood preservative pentachlorophenol. However, the underlying molecular mechanism remains unclear. Here N-methylacetohydroxamic acid (N-MeAHA) was synthesized and used as a simple model compound of DFO for further mechanistic study. As expected, direct ESR studies showed that nitroxide radical of N-MeAHA (Ac-(CH3)NO•) can be produced from N-MeAHA/TCHQ. Interestingly and unexpectedly, when TCHQ was substituted by its oxidation product tetrachloro-1,4-benzoquinone (TCBQ), although Ac-(CH3)NO• could also be produced, no concurrent formation of tetrachlorosemiquinone radical (TCSQ•) and TCHQ was detected, suggesting that Ac-(CH3)NO• did not result from direct oxidation of N-MeAHA by TCSQ• or TCBQ as proposed previously. To our surprise, a new nitrogen-centered amidyl radical was found to be generated from N-MeAHA/TCBQ, which was observed by ESR with the spin-trapping agents and further unequivacally identified as Ac-(CH3)N• by HPLC-MS. The final product of amidyl radical was isolated and identified as its corresponding amine. Analogous radical homolysis mechanism was observed with other halogenated quinoid compounds and N-alkyl hydroxamic acids including DFO. Interestingly, amidyl radicals were found to induce both DNA strand breaks and DNA adduct formation, suggesting that N-alkyl hydroxamic acids may exert their potential side-toxic effects via forming the reactive amidyl radical species. This study represents the first report of an unexpected new pathway for nitroxide radical production via hydrogen abstration reaction of a more reactive amidyl radical intermediate during the detoxification of the carcinogenic polyhalogenated quinones by N-alkyl hydroxamic acids, which provides more direct experimental evidence to better explain not only our previous finding that excess DFO can provide effective but only partial protection against TCHQ (or TCBQ)-induced biological damage, and also the potential side-toxic effects induced by DFO and other N-alkyl hydroxamic acid drugs.

Optimization of transdermal deferoxamine leads to enhanced efficacy in healing skin wounds

Chronic wounds remain a significant burden to both the healthcare system and individual patients, indicating an urgent need for new interventions. Deferoxamine (DFO), an iron-chelating agent clinically used to treat iron toxicity, has been shown to reduce oxidative stress and increase hypoxia-inducible factor-1 alpha (HIF-1α) activation, thereby promoting neovascularization and enhancing regeneration in chronic wounds. However due to its short half-life and adverse side effects associated with systemic absorption, there is a pressing need for targeted DFO delivery. We recently published a preclinical proof of concept drug delivery system (TDDS) which showed that transdermally applied DFO is effective in improving chronic wound healing. Here we present an enhanced TDDS (eTDDS) comprised exclusively of FDA-compliant constituents to optimize drug release and expedite clinical translation. We evaluate the eTDDS to the original TDDS and compare this with other commonly used delivery methods including DFO drip-on and polymer spray applications. The eTDDS displayed excellent physicochemical characteristics and markedly improved DFO delivery into human skin when compared to other topical application techniques. We demonstrate an accelerated wound healing response with the eTDDS treatment resulting in significantly increased wound vascularity, dermal thickness, collagen deposition and tensile strength. Together, these findings highlight the immediate clinical potential of DFO eTDDS to treating diabetic wounds. Further, the topical drug delivery platform has important implications for targeted pharmacologic therapy of a wide range of cutaneous diseases.

Abstract 2616: A novel iron-chelating agent reduces MYC transcription via E2F gene family regulation

Abstract Childhood neuroblastoma, a disease of the sympathetic nervous system, is the most common solid tumour of infancy. Amplification of the MYCN oncogene, which occurs in approximately 25% of patients with neuroblastoma, is one of the most powerful independent prognostic markers for this disease. MYCN belongs to the Myc gene family that codes for transcription factors often aberrantly expressed in both solid and liquid malignancies. However, despite their importance in adult and childhood malignancies, Myc oncoproteins have to date proven to be ‘undruggable’. Using a chemical library of 34,000 compounds we aimed to identify novel MYCN inhibitors, and among a number of molecules identified, M606 was found to markedly reduce MYCN protein levels as well as its downstream targets in MYCN-amplified SK-N-BE(2)-C neuroblastoma cells. Bioinformatic analysis of signalling pathways affected by M606 using FACTORIAL™ technology (Attagene Inc) demonstrated that this compound inhibits Myc-mediated transcription and simultaneously activates the HIF1α pathway. MYCN/MYC protein and mRNA stability were unaltered whereas their mRNA levels were significantly decreased. Metabolomics analysis suggested that the mechanism by which M606 inhibits MYCN transcription involves its capacity to chelate iron and, in this regard, M606-mediated inhibition of MYCN was reversed by the addition of iron. Progressive deletions of the MYCN promoter in luciferase reporter assays identified a minimal promoter region responsive to M606 that contains two E2F sites. Microarray assays performed on SK-N-BE(2)-C cells after M606 treatment showed significant changes in the expression level of the E2F gene family. Chromatin immune precipitation (ChIP) and gel shift (EMSA) assays revealed a reduction in E2F binding at the MYCN promoter region after M606 treatment. Moreover, western blot analysis showed that the RB protein, which is involved in E2F binding and transcriptional activation, becomes inactive due to hypophosphorylation following M606 treatment. On the other hand, M606 lost its inhibitory activity on a pRB-deficient osteosarcoma cell line SAOS-2, underlying the importance of the RB/E2F axis for M606 function. In conclusion, M606 is a novel Myc inhibitor and iron chelator that directly downregulates MYCN/MYC transcription via the E2F signalling pathway, providing a potentially valuable therapeutic approach in the treatment of cancers overexpressing Myc oncoproteins. Citation Format: Emanuele Valli, Chengyuan Xue, Leanna Cheung, Laura Gamble, Ruby Pandher, Simone Di Giacomo, Catherine Burkhart, Natalia Fedtsova, Francesca Ferrucci, Sergei Makarov, Thomas Telfer, Rachel Codd, David Scott, Giovanni Perini, Andrei Osterman, Andrei Gudkov, Murray Norris, Michelle Haber. A novel iron-chelating agent reduces MYC transcription via E2F gene family regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2616.

Iron-Dependent Trafficking of 5-Lipoxygenase and Impact on Human Macrophage Activation.

5-lipoxygenase (5-LOX) is a non-heme iron-containing dioxygenase expressed in immune cells that catalyzes the two initial steps in the biosynthesis of leukotrienes. It is well known that 5-LOX activation in innate immunity cells is related to different iron-associated pro-inflammatory disorders, including cancer, neurodegenerative diseases, and atherosclerosis. However, the molecular and cellular mechanism(s) underlying the interplay between iron and 5-LOX activation are largely unexplored. In this study, we investigated whether iron (in the form of Fe3+ and hemin) might modulate 5-LOX influencing its membrane binding, subcellular distribution, and functional activity. We proved by fluorescence resonance energy transfer approach that metal removal from the recombinant human 5-LOX, not only altered the catalytic activity of the enzyme, but also impaired its membrane-binding. To ascertain whether iron can modulate the subcellular distribution of 5-LOX in immune cells, we exposed THP-1 macrophages and human primary macrophages to exogenous iron. Cells exposed to increasing amounts of Fe3+ showed a redistribution (ranging from ~45 to 75%) of the cytosolic 5-LOX to the nuclear fraction. Accordingly, confocal microscopy revealed that acute exposure to extracellular Fe3+, as well as hemin, caused an overt increase in the nuclear fluorescence of 5-LOX, accompanied by a co-localization with the 5-LOX activating protein (FLAP) both in THP-1 macrophages and human macrophages. The functional relevance of iron overloading was demonstrated by a marked induction of the expression of interleukin-6 in iron-treated macrophages. Importantly, pre-treatment of cells with the iron-chelating agent deferoxamine completely abolished the hemin-dependent translocation of 5-LOX to the nuclear fraction, and significantly reverted its effect on interleukin-6 overexpression. These results suggest that exogenous iron modulates the biological activity of 5-LOX in macrophages by increasing its ability to bind to nuclear membranes, further supporting a role for iron in inflammation-based diseases where its homeostasis is altered and suggesting further evidence of risks related to iron overload.

Olfactory Dysfunction in β Thalassemia Major Patients Treated With Iron-Chelating Agents.

Ocular and ophthalmological adverse effects may be seen in β-thalassemia major (BTM) patients treated with regular blood transfusions and iron-chelating agents. We hypothesized that olfactory dysfunction may be present in this population. In this study, we aimed to investigate olfactory dysfunction in patients with BTM and determine the etiological factors. A total of 43 patients with BTM were included in the study. Forty-three patients without any nasal complaints, history of facial trauma, or nasal surgery were included as the controls. All participants had nasal endoscopy. The iron-chelating agents used, their duration of use, as well as hemoglobin and ferritin levels of the BTM patients were recorded. Sniffin' Sticks test (SST) was used to assess olfactory functions, and BTM and control groups were compared for the results. The correlations of SST scores with the other study parameters were analyzed. Eight (18.6%) of 43 patients in the BTM group had hyposmia while none of the patients in the control group had hyposmia (P < .001). Older age, low-hemoglobin level, and longer use of deferoxamine were found to be correlated with olfactory dysfunction. Olfactory dysfunction may be seen in BTM patients treated with iron-chelating agents. The results of this study suggest that screening for olfactory function may be needed in routine follow-up of BTM patients.

Comparison of five bacterial strains producing siderophores with ability to chelate iron under alkaline conditions

Iron deficiency is one of the main causes of chlorosis in plants, which leads to losses in field crops quality and yield. The use of synthetic chelates to prevent or correct iron-deficiency is not satisfactory mainly due to their poor biodegradability. The present work aimed to search suitable microorganisms to produce alternative, environment-friendly iron-chelating agents (siderophores). For this purpose, the performance of five bacteria (Azotobacter vinelandii, Bacillus megaterium, Bacillus subtilis, Pantoea allii and Rhizobium radiobacter) was evaluated, regarding siderophore production kinetics, level of siderophore production (determined by chrome azurol S, CAS method), type of siderophore produced (using Arnow and Csaky’s tests) and iron-chelating capacity at pH 9.0. All bacteria were in stationary phase at 24 h, except A. vinelandii (at 72 h) and produced the maximum siderophore amount (80–140 µmol L−1) between 24 and 48 h, with the exception of A. vinelandii (at 72 h). The analysis of culture filtrates revealed the presence of catechol-type siderophores for B. subtilis and R. radiobacter and hydroxamate-type siderophores for B. megaterium and P. allii. In the case of A. vinelandii, both siderophore-types (catechol and hydroxamates) were detected. The highest iron-chelating capacity, at pH 9.0, was obtained by B. megaterium followed by B. subtilis and A. vinelandii. Therefore, these three bacteria strains are the most promising bacteria for siderophore production and chlorosis correction under alkaline conditions.

Enhanced Degradation of Phenol by a Fenton-Like System (Fe/EDTA/H2O2) at Circumneutral pH

This work deals with the degradation of phenol based on the classical Fenton process, which is enhanced by the presence of chelating agents. Several iron-chelating agents such as ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), diethylenetriamine pentaacetic acid (DTPA), and ethylenediamine-N,N’-diacetic acid (EDDA) were explored, although particular attention was given to EDTA. The effect of the molar ligand to iron ratio, EDTA:Fe, initial pH, and temperature on the oxidation process was studied. The results demonstrate that the proposed alternative approach allows the capacity for degrading phenol to be extended from the usual acidic pH (around 3.0) to circumneutral pH range (6.5–7.5). The overall feasibility of the process depends on the concentration of the chelating agent and the initial pH of the solution. The maximum phenol conversion, over 95%, is achieved using a 0.3 to 1 molar ratio of EDTA:Fe, stoichiometric ratio of H2O2 at an initial pH of 7.0, and a temperature of 30 °C after 2 hours of reaction, whereas only 10% of phenol conversion is obtained without EDTA. However, in excess of ligand (EDTA:Fe &gt; 1), the generation of radicals seems to be strongly suppressed. Improvement of the phenol removal efficiency at neutral pH also occurs for the other chelating agents tested.

New Advances in Evaluation of Hearing in a Sample of Egyptian Children with β-Thalassemia Major.

AIM:To evaluate hearing in β-thalassemia major patients on iron chelation therapy by using pure-tone audiometry (PTA) and distortion product otoacoustic emissions (DPOAE).SUBJECTS AND METHODS:This cross-sectional, descriptive study was done on (48) diagnosed, 6-18 years old, β-thalassemia major patients who had received at least 3 years iron chelating agent deferoxamine (DFO). We performed PTA, DPOAE testing, and tympanometry for all participants. SPSS was used to analyse data. P < 0.05 was accepted as statistically significant.RESULTS:No significant difference was found between PTA and DPOAE testing in their capability to detect ototoxicity. PTA and DPOAE testing for the detection of ototoxicity in BTM and BTI, kappa values (κ) were found to be 0.516 and 0.459, respectively. The whole mean serum ferritin level was 2,251.3 ng/ml. The mean level was 1,603 ± 1,380 ng/ml in the patients with SNHL and 2,405 ± 1,908 ng/ml in the patients with normal hearing with the statistically significant difference among both groups (p = 0.015). The occurrence of ototoxicity was statistically significant with increasing age (p < 0.001). There was no marked difference as regards gender (p = 0.72).CONCLUSION:Hearing loss is prevailing in patients with β-thalassemia major on iron chelating agents. Therefore, regular hearing evaluations and periodic check-ups after the initiation of chelation therapy are mandatory.

Anticancer activity of the thiosemicarbazones that are based on di-2-pyridine ketone and quinoline moiety

Thiosemicarbazones (TSC) are a subclass of iron-chelating agents that are believed to have an anticancer activity. The high potential for the application of this compound class can be illustrated by a fact that three TSC have entered clinical trials. The ability to chelate metal ions results in several biochemical changes in the cellular metabolism and growth. An important factor that determines the antitumor activity of TSC is a level of iron regulatory proteins and the antioxidant potential that is specific for each type of cancer cell. However, despite the increasing interest in TSC, their mechanism of anticancer activity is still unclear. For a more effective and rational design, it is crucial to determine and describe the abovementioned issues. In this report, we describe a series of new TSC that are designed on the four main structural scaffolds. The anticancer activity of these compounds was evaluated against a panel of cancer cell lines including colon and breast cancers and gliomas. Special attention was paid to the metal-dependent proteins. The impact of the tested TSC on the cell cycle and redox homeostasis was also determined. These results confirm a p53-independent mechanism of apoptosis.

Cardioprotective Potential of Iron Chelators and Prochelators.

Heart is a particularly sensitive organ to iron overload and cardiomyopathy due to the excessive cardiac iron deposition causes most deaths in disorders such as beta-thalassemia major. Free or loosely bound iron ions readily cycle between ferrous and ferric states and catalyze Haber-Weiss reaction that yields highly reactive and toxic hydroxyl radicals. Treatment with iron chelators (desferrioxamine, deferiprone, and deferasirox) substantially improved cardiovascular morbidity and mortality in iron overloaded patients. Furthermore, iron chelators have been studied in various cardiovascular disorders with known or presumed oxidative stress roles (e.g., ischemia/reperfusion injury) also in patients with normal body iron contents. The pharmacodynamic and pharmacokinetic properties of these chelators are critical for effective therapy. For example, the widely clinically used but hydrophilic chelator desferrioxamine suffers from poor plasma membrane permeability, which means that high and clinically unachievable concentrations/doses must be employed to obtain cardioprotection. Therefore, small-molecular and lipophilic chelators with oral availability are more suitable for this purpose, particularly in states without systemic iron overload. Apart from agents that are already used in clinical practice, aroylhydrazone iron chelators, namely salicylaldehyde isonicotinoyl hydrazone (SIH), have provided promising results. However, the use of classical iron-chelating agents is associated with a risk of toxicity due to indiscriminate iron depletion. Recent studies have therefore focused on "masked" prochelators that have little or no affinity for iron until site-specific activation by reactive oxygen species.

Effect of Combination of Hydroxyurea and Iron Chelation Therapy on Leukocyte DNA Damage in Sickle Cell Anemia Patients

Background: Multiple organ damage has been exhibited among patients with Sickle Cell Disease due to repeated vascular occlusion, which is superimposed on a background of failure and poor development. The burden of sickle cell anemia has been potentially associated to the high prevalence of consanguineous marriages in Saudi Arabia. The aim of this study was to evaluate the effect of combination between Hydroxyurea and iron chelation therapy on the degree of DNA damage. Methods: Between September 2017 and May 2018, 96 of homozygous sickle cell anemia patients and 24 healthy controls were enrolled in the study, aged between 10-40 years. All participants were visitors of the Haematology clinic and Day Care Unit at King Abdulaziz University Hospital, Jeddah Saudi Arabia who have been diagnosed with SCA disease. The experimental groups were divided into five groups: Healthy, SCA patients who do not take any medications, SCA patients who are taking Hydroxyurea only, SCA patients who take iron-chelating agents and SCA patients who take Hydroxyurea medication with iron chelating agents. Findings: The results give a significant decrease (P<0.000) in DNA damage in patients taking Hydroxyurea with iron chelating agents compared with patients taking Hydroxyurea only (1.32 ± 1.51 and 6.36 ± 2.36; respectively). The fetal hemoglobin (HbF) levels of both of the patient treated with Hydroxyurea and iron chelating agent samples were considerably higher than all other groups while the positive control SCA patients group was having the least amount. Patients who subjected to Hydroxyurea and/or chelating agents have the least counts among all of the groups in terms of RBC's counts. When compared to the normal group, Eosinophils and lymphocytes have the greatest amount in SCA patients treated with iron chelating agent only and SCA patients treated with Hydroxyurea and iron chelation therapy compared to the normal and SCA patients who were subjected to Hydroxyurea treatment only groups; whereas, the SCA patients treated with iron chelating agent only and SCA patients treated with Hydroxyurea and iron chelation therapy. got raised in levels. Interpretation: The correlation of increasing levels of WBCs and SCD have been proved on a biological basis. Funding Statement: This research is not funded by any resource. Declaration of Interests: Dr. Helmi has nothing to disclose., and the author declares no competing interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Ethics Approval Statement: Signed consent forms were obtained from all patients and controls according to Ethics Committee guidelines protocol by the Ministry of Health in Saudi Arabia (H-02-J-002). Written informed consent was obtained from all patients and controls in accordion with the guidelines of the Ethics Committee at King Abdul Aziz University Hospital. With Ethical approval number 151- 17.

Improved survival outcomes and restoration of graft-vs-leukemia effect by deferasirox after allogeneic stem cell transplantation in acute myeloid leukemia.

Deferasirox is an oral iron‐chelating agent having possible antileukemia and immune modulatory effects. Few reports have evaluated deferasirox in the setting of allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We investigated the impact of deferasirox after allo‐HSCT in acute myeloid leukemia (AML). Of 326 consecutive patients undergoing allo‐HSCT in remission, analysis of 198 patients not receiving deferasirox revealed the negative prognostic effect of hyperferritinemia (≥1000 ng/mL) before and after allo‐HSCT on survival mainly due to increase in relapse. Of 276 patients with hyperferritinemia at 1 month after allo‐HSCT, 128 patients (46%) received deferasirox. Deferasirox induced a faster decline in serum ferritin level with a manageable safety profile, which significantly reduced relapse rather than nonrelapse mortality, resulting in better survival compared to patients not receiving deferasirox. Of note, the deferasirox group had a significantly higher incidence of chronic graft‐vs‐host disease, indicating improved graft‐vs‐leukemia (GVL) effects evidenced by the presence of suppressed regulatory T cells and sustained higher proportion of NK cells in peripheral blood. This study firstly demonstrates the improved survival and restoration of GVL effects of patients with AML by deferasirox, which also clarifies the detrimental effect of hyperferritinemia through after allo‐HSCT.

Novel Coumarin‐Quinoline Hybrids: Design of Multitarget Compounds for Alzheimer's Disease

AbstractAlzheimer's disease (AD) is the most prevalent neurodegenerative disease, presenting the most devastating consequences on human health and life quality. Coumarin‐quinoline hybrids were synthesized following a very efficient and versatile strategy. Small structural variations contributed to dual acetyl/butyrylcholinesterases (AChE/BuChE) activity or selectivity towards one of these enzymes. In addition, some of the studied compounds are interesting iron chelators, presenting a tendency to be neuroprotective. Moreover, the compounds are not cytotoxic for SH‐SY5Y neuroblastoma cells. Compound 9c proved to be the most interesting compound of the studied series. This compound is selective against AChE and proved to be an excellent iron chelating agent (iron chelation at 100 μM=72.87%). Molecular docking studies were performed to establish the nature of the interaction between the studied compounds and the binding pockets, leading to a rationalization of structure–activity relationships. Compound 9c forms a well‐defined π‐stacking interaction with Phe330 and interacts with Tyr121 residue via a hydrogen bond, while the inactive compounds cannot establish these interactions. Important preliminary results against different targets, as well as some structure–activity relationships, were concluded from the experimental results.

New hexadentate tris(dopamine) as iron chelating agent: Synthesis, solution thermodynamic stability and antioxidant activity studies

There is a growing interest in the development of new iron ligands as novel promising therapeutic strategies for neurodegenerative disorders. In the article, a new tripodal hexadentate tris(dopamine) ligand, containing three dopamine chelate moieties which were attached to a cyanuric chloride molecular scaffold, has been synthesized and fully characterized by NMR, FTIR and MS. The solution thermodynamic stability of the ligand with FeIII, MgII and ZnII ions was investigated. The results demonstrated that the ligand exhibited effective binding ability and improved selectivity for FeIII ion. The high affinity could be attributed to the favorable geometric arrangement between the ligand and FeIII ion coordination preference. The ligand also exhibited high antioxidant activity. Hence, the ligand could be used as potential chelating agent for iron overload situations.

Study of the effect of different iron-chelating agents on early renal glomerular and tubular function markers in children with beta-thalassemia

Background Advances in the management of patients of beta-thalassemia major (BTM) and the advent of effective chelators have led to the discovery of many renal complications. Mechanisms of renal impairment in BTM are still not fully investigated. Chronic anemia and hypoxia, iron overload and its complications, and direct nephrotoxic effects of some chelators are the commonly used explanations. Objectives In this cross-sectional study, the aim was to investigate the prevalence of renal impairment in patients with BTM using some of both conventional and early markers of glomerular and tubular renal function and to investigate the relation between them and iron overload (s. ferritin) and the use of a specific chelator. Patients and methods The study included 60 transfusion-dependent patients with BTM without overt renal disease or risk factors, for example, diabetes mellitus, and 30 age-matched and sex-matched healthy children as a control group (group C). Patients were divided into two equal groups according to type of chelator: group A children receiving standard deferoxamine (DFO) and/or deferiprone and group B children receiving deferasirox (new treatment). Serum levels of ferritin, creatinine, and blood urea nitrogen; albumin/creatinine ratio (ACR) in urine; estimated glomerular filtration rate using Schwartz formula; urinary beta 2 microglobulin (UB2MG); and urinary calcium/creatinine ratio were measured in all patients and healthy control children. Results Serum creatinine was within the normal range in most of the patients, and no significant differences were found between the two thalassemic groups and the control group (P=0.473). ACR in urine and UB2MG were significantly higher in the two thalassemic groups, and the deferasirox group showed significantly higher levels than both DFO and/or deferiprone group and control group (P1=0.05 and P2=0.005, respectively, for ACR and P1=0.025 and P2=0.000, respectively, for UB2MG). UB2MG was abnormally high in 67 and 76% of the DFO and/or deferiprone group and deferasirox group, respectively, followed by microalbuminuria (16 and 30%, respectively). Glomerular hyperfiltration was prevalent, but there were no significant differences in the median of the three groups (P=0.766). Hypercalciuria was also prevalent in the two thalassemic groups with abnormally elevated urinary calcium/creatinine ratio in 30% of both groups but without significant differences in the median of the three groups (P=0.123). Serum ferritin was significantly positively correlated with ACR (P=0.002) and with UB2MG (P=0.000). Conclusions ACR can be used as an early marker of glomerular function. Deferasirox use is probably safe in the usual doses in low-risk patients, keeping into consideration that high doses of deferasirox cause disruption of the renal function.

Early Predictors of Renal Dysfunction in Pediatric Patients with Sickle Cell Disease.

Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by abnormal hemoglobin production which leads to hemolytic anemia and intermittent occlusion of small blood vessels, which further leads to tissue ischemia, chronic organ damage, and organ dysfunction including urinary system. To measure the serum levels of cystatin-C and beta 2 microglobulin in pediatric patients with SCDand to investigate their significance as early biomarkers of glomerular and/or renal tubular dysfunction. This study was conducted among 70 children with SCD and 40 age and sex-matched children as a control group. All subjects underwent a full medical history, through physical examination, laboratory investigations including blood urea, serum creatinine, serum ferritin, estimated glomerular filtration rate (eGFR) using the Schwartz formula, creatinine clearance, urinary albumin/creatinine ratio, serum cystatin-C, and β-2 microglobulin levels. Pediatric patients with SCD had significantly higher serum cystatin-C and β-2 microglobulin levels compared to controls. In addition, serum cystatin-C and β-2 microglobulin levels were positively correlated with blood urea, serum creatinine, serum ferritin, urinary albumin/creatinine ratio, duration of iron chelating agents and frequency of blood transfusion/year. Serum cystatin-C and β-2 microglobulin levels were negatively correlated with hemoglobin. Our data concluded that serum cystatin-C and β-2 microglobulin had highersensitivity and specificity (91%, 90% and 85.7%, 100%, respectively) than serum creatinine (79% and85%, respectively). Serum Cystatin-C and β-2 microglobulin are early specific and sensitive biomarkers for evaluating glomerular and tubular dysfunction in children with SCD.

Body iron accumulation in obesity, diabetes and its complications, and the possibility of therapeutic application by iron regulation

Iron is an essential trace metal element for maintaining vital functions, and it is involved in hemoglobin synthesis, redox reaction, enzyme activity, cell proliferation and apoptosis in various cells. Iron deficient-related diseases represented anemia are well-known, on the other hand, iron overload disease has attracted little attention. Excessive iron produces hydroxyl radicals via Fenton/Haber-Weiss reaction, causing organ damage in hereditary iron overload diseases. Additionally, it has been clarified that iron accumulation is involved in the pathological conditions even in metabolic diseases thought to be unrelated to iron so far. Therefore, the role of iron in the living body has been raised attention again. Recent studies have reported that body iron content is associated with both obesity and diabetes, and iron might be an aggravating factor of obesity and diabetes. We have revealed that iron chelating agent reduced oxidative stress and inflammation, suppressing the development of adipose hypertrophy in KKAy mice. Dietary iron restriction also diminishes oxidative stress, leading to the inhibition of increased albuminuria excretion and glomerular lesions in db/db mice. In this review, we give an outline of the role of iron on obese and diabetes, and diabetic kidney disease, and present the possibility of application to treatment with iron regulation in those disorders.