Synthesis, anticancer activity, and molecular docking of half-sandwich iron(II) cyclopentadienyl complexes with maleimide and phosphine or phosphite ligands.

In these studies, we designed and investigated the potential anticancer activity of five iron(II) cyclopentadienyl complexes bearing different phosphine and phosphite ligands. All complexes were characterized with spectroscopic analysis viz. NMR, FT-IR, ESI-MS, UV-Vis, fluorescence, XRD (for four complexes) and elemental analyses. For biological studies, we used three types of cells-normal peripheral blood mononuclear (PBM) cells, leukemic HL-60 cells and non-small-cell lung cancer A549 cells. We evaluated cell viability and DNA damage after cell incubation with these complexes. We observed that all iron(II) complexes were more cytotoxic for HL-60 cells than for A549 cells. The complex CpFe(CO)(P(OPh)3)(η1-N-maleimidato) 3b was the most cytotoxic with IC50 = 9.09 µM in HL-60 cells, IC50 = 19.16 µM in A549 and IC50 = 5.80 µM in PBM cells. The complex CpFe(CO)(P(Fu)3)(η1-N-maleimidato) 2b was cytotoxic only for both cancer cell lines, with IC50 = 10.03 µM in HL-60 cells and IC50 = 73.54 µM in A549 cells. We also found the genotoxic potential of the complex 2b in both types of cancer cells. However, the complex CpFe(CO)2(η1-N-maleimidato) 1 which we studied previously, was much more genotoxic than complex 2b, especially for A549 cells. The plasmid relaxation assay showed that iron(II) complexes do not induce strand breaks in fully paired ds-DNA. The DNA titration experiment showed no intercalation of complex 2b into DNA. Molecular docking revealed however that complexes CpFe(CO)(PPh3) (η1-N-maleimidato) 2a, 2b, 3b and CpFe(CO)(P(OiPr)3)(η1-N-maleimidato) 3c have the greatest potential to bind to mismatched DNA. Our studies demonstrated that the iron(II) complex 1 and 2b are the most interesting compounds in terms of selective cytotoxic action against cancer cells. However, the cellular mechanism of their anticancer activity requires further research.

Deciphering the Diversified Metabolic Behavior of Hydroxyalkyl Ferrocidiphenols as Anticancer Complexes.

Ferrocidiphenols possessing appropriate substituents in the aliphatic chain have very promising anticancer properties, but a systematic approach to deciphering their diversified metabolic behavior has so far been lacking. Herein, we show that a series of novel ferrocidiphenols bearing different hydroxyalkyl substituents exhibit strong anticancer activity as revealed in a range of in vitro and in vivo experiments. Moreover, they display diversified oxidative transformation profiles very distinct from those of previous complexes, shown by the use of chemical and enzymatic methods and in cellulo and in vivo metabolism studies. In view of this phenomenon, unprecedented chemo-evolutionary sequences that connect all the ferrocidiphenol-related intermediates and analogues have been established. In addition, a comprehensive density functional theory (DFT) study has been performed to decipher the metabolic diversification profiles of these complexes and demonstrate the delicate modulation of carbenium ions by the ferrocenyl moiety, via either α- or ß-positional participation.

Oxidation-derived anticancer potential of sumanene-ferrocene conjugates.

An effective synthetic protocol towards the oxidation of sumanene-ferrocene conjugates bearing one to four ferrocene moieties has been established. The oxidation protocol was based on the transformation of FeII from ferrocene to FeIII-containing ferrocenium cations by means of the treatment of the title organometallic buckybowls with a mild oxidant. Successful isolation of these ferrocenium-tethered sumanene derivatives 5-7 gave rise to the biological evaluation of the first, buckybowl-based anticancer agents, as elucidated by in vitro assays with human breast adenocarcinoma cells (MDA-MB-231) and embryotoxicity trials in zebrafish embryos supported with in silico toxicology studies. The designed ferrocenium-tethered sumanene derivatives featured attractive properties in terms of their use in cancer treatments in humans. The tetra-ferrocenium sumanene derivative 7 featured especially beneficial biological features, elucidated by low (<40% for 10 µM) viabilities of MDA-MB-231 cancer cells together with a 1.4-1.7-fold higher viability of normal cells (human mammary fibroblasts, HMF) for respective concentrations. Compound 7 featured significant cytotoxicity against cancer cells thanks to the presence of sumanene and ferrocenium moieties; the latter motif also provided the selectivity of anticancer action. The biological properties of 7 were also improved in comparison with those of native building blocks, which suggested the effects of the presence of the sumanene skeleton towards the anticancer action of this molecule. Ferrocenium-tethered sumanene derivatives exhibited potential towards the generation of reactive oxygen species (ROS), responsible for biological damage to the cancer cells, with the most efficient generation of the tetra-ferrocenium sumanene derivative 7. Derivative 7 also did not show any embryotoxicity in zebrafish embryos at the tested concentrations, which supports its potential as an effective and cancer-specific anticancer agent. In silico computational analysis also showed no chromosomal aberrations and no mutation with AMES tests for the compound 7 tested with and without microsomal rat liver fractions, which supports its further use as a potent drug candidate in detailed anticancer studies.

Iron(II)-cyclopentadienyl compounds are cytotoxic against colon adenocarcinoma cell lines: Ethylenebis(diphenylphosphane) vs. triphenylphosphane.

Structure-activity studies aiming to understand the role of each coligand in the formulation of new metallodrugs is an important subject. In that frame, six new compounds with general formula [Fe(η5-C5H5)(dppe)(L)][CF3SO3] with L = benzonitriles (1-4) or carbon monoxide (5) and compound [Fe(η5-C5H5)(CO)(PPh3)2][CF3SO3] (6) were synthesized and compared with three other previously reported compounds [Fe(η5-C5H5)(CO)(L)(PPh3)][CF3SO3]. We were particularly interested in assessing the effect of dppe vs. (PPh3 + CO) for this set of compounds. For that, all compounds were tested against two human colon adenocarcinoma cell lines, Colo205 and the refractile Colo320 (expressing ABCB1, an efflux pump causing multidrug resistance), showing IC50 values in the micromolar range. The presence of dppe in the compound's coordination sphere over (PPh3 + CO) allows for more redox stable compounds showing higher cytotoxicity and selectivity, with improved cytotoxicity towards resistant cells that is not related to the inhibition of ABCB1. Further studies with GSH and H2O2 for selected compounds indicated that their antioxidant ability is not probably the main responsible for their cytotoxicity.

Oxidation-Resistant Silicon Nanosystem for Intelligent Controlled Ferrous Foliar Delivery to Crops.

Since ferrous (Fe(II)) is the main form of plant absorption, traditional ferrous foliar fertilizers (TFFF) are widely used in modern agriculture. However, TFFF suffer from the shortcomings of weak antioxidant capacity (AC), low foliar adhesion efficiency (FAE), poor fertilizer utilization efficiency (FUE), and noncontrollable slow-release behavior. To overcome these limitations, an oxidation-resistant silicon nanosystem for intelligent controlled ferrous foliar delivery to crops was first developed by using environmentally friendly micro/nano structured hollow silicon as carrier, and combining with vitamin C (in situ antioxidant) to synthesize an oxidation-resistant ferrous foliar fertilizer (ORFFF) for ameliorating Fe-deficiency in crops and increasing crop yield. Compared with TFFF, the ORFFF has excellent ferrous AC (only 11.5% of Fe(II) was oxidized in ORFFF within 72 h), ultrahigh FAE (∼84% of adhesion percentage (%) after two-times simulated rain rinsing), nutrient slow-release ability (720 h gradually release 100.6 mg·g-1), pH-controlled release ability (pH 3-8), and verified high biological safety (100% survival rate for zebrafish and earthworm). The pot experiments showed that ORFFF can correct the Fe-deficiency symptoms of tomato seedlings promptly compared with TFFF, and the FUE of ORFFF is 4.2 times that of TFFF. The specific pH responsiveness of ORFFF can control the slow-release rate of Fe(II) to satisfy the needs of Fe in varying crops and different growing periods of crops. This work provides a feasible way to achieve green and safe Fe supplementation for crops, reduce Fe fertilizer waste, avoid soil pollution caused by Fe fertilizer abuse, and promote the sustainable development of modern nanoagriculture.

First iron(II) organometallic compound acting as ABCB1 inhibitor.

Five new iron (II) complexes bearing imidazole-based (Imi-R) ligands with the general formula [Fe(η5-C5H5)(CO)(PPh3)(Imi-R)][CF3SO3] were synthesized and fully characterized by several spectroscopic and analytical techniques. All compounds crystallize in centrosymmetric space groups in a typical "piano stool" distribution. Given the growing importance of finding alternatives to overcome different forms of multidrug resistance, all compounds were tested against cancer cell lines with different ABCB1 efflux pump expression, namely, the doxorubicin-sensitive (Colo205) and doxorubicin-resistant (Colo320) human colon adenocarcinoma cell lines. Compound 3 bearing 1-benzylimidazole was the most active in both cell lines with IC50 values of 1.26 ± 0.11 and 2.21 ± 0.26 µM, respectively, being also slightly selective against the cancer cells (vs. MRC5 normal human embryonic fibroblast cell lines). This compound, together with compound 2 bearing 1H-1,3-benzodiazole, were found to display very potent ABCB1 inhibitory effect. Compound 3 also showed the ability to induce cell apoptosis. Iron cellular accumulation studies by ICP-MS and ICP-OES methods revealed that the compounds' cytotoxicity is not related to the extent of iron accumulation. Yet, it is worth mentioning that, from the compounds tested, 3 was the only one where iron accumulation was greater in the resistant cell line than in the sensitive one, validating the possible role of ABCB1 inhibition in its mechanism of action.

Cinnamomum zeylanicum Blume Essential Oil Inhibits Metastatic Melanoma Cell Proliferation by Triggering an Incomplete Tumour Cell Stress Response.

Given the known pro-oxidant status of tumour cells, the development of anti-proliferative strategies focuses on products with both anti- and pro-oxidant properties that can enhance antitumour drug cytotoxicity. We used a C. zeylanicum essential oil (CINN-EO) and assessed its effect on a human metastatic melanoma cell line (M14). Human PBMCs and MDMs from healthy donors were used as normal control cells. CINN-EO induced cell growth inhibition, cell cycle perturbation, ROS and Fe(II) increases, and mitochondrial membrane depolarization. To assess whether CINN-EO could affect the stress response, we analysed iron metabolism and stress response gene expression. CINN-EO increased HMOX1, FTH1, SLC7A11, DGKK, and GSR expression but repressed OXR1, SOD3, Tf, and TfR1 expression. HMOX1, Fe(II), and ROS increases are associated with ferroptosis, which can be reversed by SnPPIX, an HMOX1 inhibitor. Indeed, our data demonstrated that SnPPIX significantly attenuated the inhibition of cell proliferation, suggesting that the inhibition of cell proliferation induced by CINN-EO could be related to ferroptosis. Concurrent treatment with CINN-EO enhanced the anti-melanoma effect of two conventional antineoplastic drugs: the mitochondria-targeting tamoxifen and the anti-BRAF dabrafenib. We demonstrate that CINN-EO-mediated induction of an incomplete stress response specifically in cancer cells affects the proliferation of melanoma cells and can enhance drug cytotoxicity.

Nanoscale Two-Dimensional FeII- and CoII-Based Metal-Organic Frameworks of Porphyrin Ligand for the Photodynamic Therapy of Breast Cancer.

The delivery of biocompatible reagents into cancer cells can elicit an anticancer effect by taking advantage of the unique characteristics of the tumor microenvironment (TME). In this work, we report that nanoscale two-dimensional FeII- and CoII-based metal-organic frameworks (NMOFs) of porphyrin ligand meso-tetrakis (6-(hydroxymethyl) pyridin-3-yl) porphyrin (THPP) can catalyze the generation of hydroxyl radicals (•OH) and O2 in the presence of H2O2 that is overexpressed in the TME. Photodynamic therapy consumes the generated O2 to produce a singlet oxygen (1O2). Both •OH and 1O2 are reactive oxygen species (ROS) that inhibit cancer cell proliferation. The FeII- and CoII-based NMOFs were non-toxic in the dark but cytotoxic when irradiated with 660 nm light. This preliminary work points to the potential of porphyrin-based ligands of transition metals as anticancer drugs by synergizing different therapeutic modalities.

Ferrocene Derivatives as New Generation of Antimalarial Agents: Opportunity or Illusion?

Despite significant scientific progress over the last two decades, malaria remains a global burden that causes thousands of deaths every year. In the absence of effective and practical preventive measures, the only current option for reducing the mortality and morbidity of malaria is chemotherapy. However, due to the minimal stock of active antiparasitic analogs, issues of toxicity, and the repeated appearance of drug resistance, scientists must broaden the arsenal of existing therapies beyond conventional medicinal chemistry. To curb this menace, a series of potential metal-based hybrids have been synthesized and screened. Ferrocene is one of the potent organometallic candidates and the hybridization of ferrocene with other pharmacophores results in compounds with enhanced biological activities. Many researchers have reported the ferrocene compounds as potent pharmacophores and useful as anticancer and antimalarial agents when hybridized with other pharmaceutical hybrids. Drug, such as Ferroquine (FQ, SSR97193), is currently the most advanced organometallic compound developed from the hybridization of ferrocene and chloroquine and has demonstrated great potency in clinical trials against both drug-sensitive and drug-resistant malaria. Not only ferroquine but its derivatives have shown significant activity as antimalarial agents. The present review focuses on the discovery of FQ, the hypothesis of its mode of action, and recent clinical trials of ferrocene compounds as a new class of antimalarial agents. The structure-activity relationship (SAR) of ferrocene derivatives is also discussed to provide insight into the rational design of more effective antimalarial candidates. Finally, efforts have been made to discuss the future expectations for ferrocene-based antimalarial drugs.

Sodium ferrous citrate and 5-aminolevulinic acid improve type 2 diabetes by maintaining muscle and mitochondrial health.

OBJECTIVE: Improving mitochondrial function is a promising strategy for intervention in type 2 diabetes mellitus. This study investigated the preventive effects of sodium ferrous citrate (SFC) and 5-aminolevulinic acid phosphate (ALA) on several metabolic dysfunctions associated with obesity because they have been shown to alleviate abnormal glucose metabolism in humans. METHODS: Six-week-old male C57BL/6J mice were fed with a normal diet, a high-fat diet, or a high-fat diet supplemented with SFC and ALA for 15 weeks. RESULTS: The simultaneous supplementation of SFC + ALA to high-fat diet-fed mice prevented loss of muscle mass, improved muscle strength, and reduced obesity and insulin resistance. SFC + ALA prevented abnormalities in mitochondrial morphology and reverted the diet effect on the skeletal muscle transcriptome, including the expression of glucose uptake and mitochondrial oxidative phosphorylation-related genes. In addition, SFC + ALA prevented the decline in mitochondrial DNA copy number by enhancing mitochondrial DNA maintenance and antioxidant transcription activity, both of which are impaired in high-fat diet-fed mice during long-term fasting. CONCLUSIONS: These findings suggest that SFC + ALA supplementation exerts its preventive effects in type 2 diabetes mellitus via improved skeletal muscle and mitochondrial health, further validating its application as a promising strategy for the prevention of obesity-induced metabolic disorders.

Iron-doped cross-linked lipoic acid nano-aggregates for ferroptosis-mediated cancer treatment.

Recently, Fenton reaction-mediated ferroptosis has attracted great attention in cancer treatment while the metabolism loss of iron and the limited endogenous H2O2 level imped its clinical application. Here, a new ferroptosis inducer (Fe@cLANAs) constructed only by Fe(II) and (R)-(+)-lipoic acid (LA) was developed for tumor ablation. After entering the tumor cells, the Fe@cLANAs dissociated into disdihydrolipoic acid (DHLA) and released iron, which would regenerate each other to continuously provide iron and H2O2 to enhance ferroptosis. The Fe@cLANAs demonstrated the IC50Fe below 10 µM against various tumor cells, an anti-tumor effect comparable to many chemotherapy drugs. In vivo antitumor evaluation based on the tumor cell-derived xenograft model showed a tumor inhibitory rate (TIR) of 97.4% at the iron usage of 1.53 mg/kg, the lowest iron usage reported so far in ferrotherapy using iron as the main agent to treat tumors. Notably, the good anti-tumor effect of Fe@cLANAs was further achieved in the glioma patient-derived xenograft (PDX) model. This strategy utilizing the reciprocal circulation of metal iron and LA to delay the metabolism loss of iron and increase the H2O2 level in the tumor cells holds a great potential for ferroptosis-mediated cancer treatment. STATEMENT OF SIGNIFICANCE: The metabolism loss of iron and the limited endogenous H2O2 level are key factors to impede the clinical application of ferroptosis-mediated cancer treatment. Herein, a new ferroptosis inducer constructed only by lipoic acid and iron is developed to delay the metabolism loss of iron and increase the level of endogenous H2O2 by causing a cyclic regeneration of Fe(II)/Fe(III) and LA/DHLA in the tumor cells. According to the previous reports, at least 75 mg/kg of iron dosage was needed to achieve effective antitumor efficacy, here, the use of only 1.53 mg/kg iron in Fe@cLANAs achieved the TIR of 97.4% and 62.8% in the U251 CDX and glioma PDX models, showing the good prospect of Fe@cLANAs in clinic.

Vitamin E protective effects on genomic and cellular damage caused by paediatric preventive supplementation for anaemia: an experimental model.

Iron deficiency is the leading cause of anaemia. In Argentina, the prevalence of anaemia and iron deficiency is very high; for that reason, the Argentine Society of Pediatrics recommends daily ferrous sulphate supplementation as a preventive treatment strategy. Alternatively, weekly ferrous sulphate supplementation has also been shown to be effective for anaemia prevention. Excess iron could be related to oxidative stress, which may in turn cause cytomolecular damage. Both can be prevented with vitamin E supplementation. We evaluated the effect of both daily and weekly ferrous sulphate supplementation combined with two doses of vitamin E on cell viability, oxidative stress and cytomolecular damage in peripheral blood cultured in vitro. The experimental design included the following groups: untreated negative control, two vitamin E controls (8·3 and 16·6 µg/ml), weekly ferrous sulphate supplementation (0·55 mg/ml) with each vitamin E dose, daily ferrous sulphate supplementation (0·14 mg/ml) with each vitamin E dose and a positive control. Daily ferrous sulphate supplementation decreased cell viability and increased the levels of reactive oxygen species, lipid peroxidation and cytomolecular damage (P < 0·5) compared with the weekly supplementation, probably due to the excess iron observed in the former. Vitamin E seemed to reduce ferrous sulphate-induced oxidative stress and genomic damage.

Molecular Hybridization Strategy on the Design, Synthesis, and Structural Characterization of Ferrocene-N-acyl Hydrazones as Immunomodulatory Agents.

Immunomodulatory agents are widely used for the treatment of immune-mediated diseases, but the range of side effects of the available drugs makes necessary the search for new immunomodulatory drugs. Here, we investigated the immunomodulatory activity of new ferrocenyl-N-acyl hydrazones derivatives (SintMed(141−156). The evaluated N-acyl hydrazones did not show cytotoxicity at the tested concentrations, presenting CC50 values greater than 50 µM. In addition, all ferrocenyl-N-acyl hydrazones modulated nitrite production in immortalized macrophages, showing inhibition values between 14.4% and 74.2%. By presenting a better activity profile, the ferrocenyl-N-acyl hydrazones SintMed149 and SintMed150 also had their cytotoxicity and anti-inflammatory effect evaluated in cultures of peritoneal macrophages. The molecules were not cytotoxic at any of the concentrations tested in peritoneal macrophages and were able to significantly reduce (p < 0.05) the production of nitrite, TNF-α, and IL-1ß. Interestingly, both molecules significantly reduced the production of IL-2 and IFN-γ in cultured splenocytes activated with concanavalin A. Moreover, SintMed150 did not show signs of acute toxicity in animals treated with 50 or 100 mg/kg. Finally, we observed that ferrocenyl-N-acyl hydrazone SintMed150 at 100 mg/kg reduced the migration of neutrophils (44.6%) in an acute peritonitis model and increased animal survival by 20% in an LPS-induced endotoxic shock model. These findings suggest that such compounds have therapeutic potential to be used to treat diseases of inflammatory origin.

Partially Reduced MIL-100(Fe) as a CO Carrier for Sustained CO Release and Regulation of Macrophage Phenotypic Polarization.

Carbon monoxide (CO) is a bioactive molecule with high potential as it shows promising efficacy for regulating inflammation. Materials capable of storing and delivering CO are of great potential therapeutic value. Although CO-releasing molecules (CORMs) have been developed to deliver CO, the short CO duration of minutes to 2 h confines their practical use. In this study, partially reduced MIL-100(Fe) as a new CO-releasing nanoMOF was developed and used for sustained CO release and macrophage (MA) phenotypic polarization regulation. MIL-100(Fe) was synthesized and mildly annealed in vacuum for partial reduction. When the annealing temperature was lower than 250 °C, less Fe(II) present in MIL-100(Fe) and the subsequent CO adsorption and desorption profiles displayed typical features of physisorption. While it was annealed at 250 °C, it showed about 20% of Fe(III) was reduced, which resulted in chemisorption of CO due to the high coordination affinity of Fe(II) to CO. The loading amount of CO was increased, and the CO release was prolonged for about 24 h. Furthermore, the CO release from this nanoMOF could alter the lipopolysaccharide (LPS)-induced macrophage from M1 to the alternative M2 phenotype and promoted the growth of endothelial cells (ECs) by paracrine regulation of MA. It can be envisioned as a promising CO-releasing solid for biomedical application.

α-Hydroxylactams as Efficient Entries to Diversely Functionalized Ferrociphenols: Synthesis and Antiproliferative Activity Studies.

The [ferrocene-ene-phenol] motif has been identified as the pharmacophore responsible for the anticancer activity of the family of ferrocene-based molecules coined ferrocifens, owing to its unique redox properties. The addition of imide entities to the historical ferrociphenol scaffold tremendously enhanced the cytotoxic activity of a large panel of cancer cell cultures and preliminary studies showed that the reduction of one of the carbonyl groups of the imide groups to the corresponding α-hydroxylactams only slightly affected the antiproliferative activity. As a continuation to these studies, we took advantage of the facile conversion of α-hydroxylactams to highly electrophilic N-acyliminium ions to graft various substituents to the imide motif of phthalimido ferrocidiphenol. Cell viability studies showed that the newly synthesized compounds showed diverse cytotoxic activities on two breast cancer cell lines, while only one compound was significantly less active on the non-tumorigenic cell line hTERT-RPE1.

Elevated Levels of Three Reactive Oxygen Species and Fe(II) in the Antibiotic-Surviving Population of Mycobacteria Facilitate De Novo Emergence of Genetic Resisters to Antibiotics.

We had earlier reported the de novo emergence of genetic resisters of Mycobacterium tuberculosis and Mycobacterium smegmatis to rifampicin and moxifloxacin from the antibiotic-surviving population containing elevated levels of the non-DNA-specific mutagenic reactive oxygen species (ROS) hydroxyl radical. Since hydroxyl radical is generated by Fenton reaction between Fe(II) and H2O2, which is produced by superoxide dismutation, we here report significantly elevated levels of these three ROS and Fe(II) in the M. smegmatis rifampicin-surviving population. Elevated levels of superoxide and the consequential formation of high levels of H2O2 and Fe(II) led to the generation of hydroxyl radical, facilitating de novo high frequency emergence of antibiotic resisters. The M. smegmatis cultures, exposed to nontoxic concentrations of the ROS scavenger, thiourea (TU), and the NADH oxidase (one of the superoxide producers) inhibitor, diphenyleneiodonium chloride (DPI), showed a reduction in the levels of the three ROS, Fe(II), and antibiotic resister generation frequency. The non-antibiotic-exposed cultures grown in the absence/presence of TU/DPI did not show increased ROS, Fe(II) levels, or antibiotic resister generation frequency. The antibiotic-surviving population showed significantly increased expression and activity of superoxide-producing genes and decreased expression of antioxidant and DNA repair genes, revealing an environment conducive for the acquisition and retention of mutations. Since we recently reported significant comparability between the antibiotic-survival gene expression profiles of the saprophyte-cum-opportunistic pathogens M. smegmatis and the M. tuberculosis in tuberculosis patients undergoing treatment, we discuss the clinical relevance of the findings on the mechanism of emergence of antibiotic-resistant mycobacterial strains.

Diversity-oriented synthesis and bioactivity evaluation of N-substituted ferrocifen compounds as novel antiproliferative agents against TNBC cancer cells.

Ferrociphenols are characterized by the presence of a biologically active redox motif [ferrocenyl-ene-p-phenol], and are known to exhibit anticancer properties. Recent studies have identified a new series of ferrociphenols that bear an imido-type heterocycle at the terminus of a short alkyl chain, and which showed very strong antiproliferativity against multiple types of cancer cells. This work describes the syntheses and an SAR study of ferrociphenols bearing a diversity-based range of nitrogen-containing substituents on the alkyl chain. Preliminary oxidative metabolism experiments and ROS-related bioactivity measurements were also carried out to probe the origin of the cytotoxicity of the imido-ferrociphenols. Furthermore, an interesting dimerization phenomenon was observed in the X-ray crystal structure of the 2,3-naphthalenedicarboximidopropyl-ferrocidiphenol, 21, which may be a factor in decreasing its rate of oxidation to form the corresponding quinone methide, 21-QM, thereby affecting its antitumor activity. These results suggest that both the formation rate and the stability of QMs could affect the antiproliferative activity of their ferrociphenol precursors.

A water-soluble iron-porphyrin complex capable of rescuing CO-poisoned red blood cells.

We describe herein a small-molecule platform that exhibits key properties needed by an antidote for CO poisoning. The design features an iron-porphyrin complex with bulky substituents above and below the macrocyclic plane to provide a hydrophobic pocket for CO binding and to prevent the formation of inactive oxo-bridged dimers. Peripheral charged groups impart water solubility. We demonstrate that the Fe(II) complex of a porphyrin with 2,6-diphenyl-4-sulfophenyl meso substituents can bind CO, stoichiometrically sequester CO from carboxyhemoglobin, and rescue CO-poisoned red blood cells.

Inhibitory effect and mechanism of gelatin stabilized ferrous sulfide nanoparticles on porcine reproductive and respiratory syndrome virus.

BACKGROUND: The infection and spread of porcine reproductive and respiratory syndrome virus (PRRSV) pose a serious threat to the global pig industry, and inhibiting the viral infection process is a promising treatment strategy. Nanomaterials can interact with viruses and have attracted much attention due to their large specific surface area and unique physicochemical properties. Ferrous sulfide nanoparticles (FeS NPs) with the characteristics of high reactivity, large specific surface area, and low cost are widely applied to environmental remediation, catalysis, energy storage and medicine. However, there is no report on the application of FeS NPs in the antiviral field. In this study, gelatin stabilized FeS nanoparticles (Gel-FeS NPs) were large-scale synthesized rapidly by the one-pot method of co-precipitation of Fe2+ and S2‒. RESULTS: The prepared Gel-FeS NPs exhibited good stability and dispersibility with an average diameter of 47.3 nm. Additionally, they were characterized with good biocompatibility and high antiviral activity against PRRSV proliferation in the stages of adsorption, invasion, and replication. CONCLUSIONS: We reported for the first time the virucidal and antiviral activity of Gel-FeS NPs. The synthesized Gel-FeS NPs exhibited good dispersibility and biocompatibility as well as effective inhibition on PRRSV proliferation. Moreover, the Fe2+ released from degraded Gel-FeS NPs still displayed an antiviral effect, demonstrating the advantage of Gel-FeS NPs as an antiviral nanomaterial compared to other nanomaterials. This work highlighted the antiviral effect of Gel-FeS NPs and provided a new strategy for ferrous-based nanoparticles against PRRSV.

Iron from nanostructured ferric phosphate: absorption and biodistribution in mice and bioavailability in iron deficient anemic women.

Food fortification with iron nanoparticles (NPs) could help prevent iron deficiency anemia, but the absorption pathway and biodistribution of iron-NPs and their bioavailability in humans is unclear. Dietary non-heme iron is physiologically absorbed via the divalent metal transporter-1 (DMT1) pathway. Using radio- iron isotope labelling in mice with a partial knockdown of intestine-specific DMT1, we assessed oral absorption and tissue biodistribution of nanostructured ferric phosphate (FePO4-NP; specific surface area [SSA] 98 m2g-1) compared to to ferrous sulfate (FeSO4), the reference compound. We show that absorption of iron from FePO4-NP appears to be largely DMT1 dependent and that its biodistribution after absorption is similar to that from FeSO4, without abnormal deposition of iron in the reticuloendothelial system. Furthermore, we demonstrate high bioavailability from iron NPs in iron deficient anemic women in a randomized, cross-over study using stable-isotope labelling: absorption and subsequent erythrocyte iron utilization from two 57Fe-labeled FePO4-NP with SSAs of 98 m2g-1 and 188 m2g-1 was 2.8-fold and 5.4-fold higher than from bulk FePO4 with an SSA of 25 m2g-1 (P < 0.001) when added to a rice and vegetable meal consumed by iron deficient anemic women. The FePO4-NP 188 m2g-1 achieved 72% relative bioavailability compared to FeSO4. These data suggest FePO4-NPs may be useful for nutritional applications.