JBIC Journal of Biological Inorganic Chemistry最新文献

Five non-symbiotic hemoglobins (nsHb) have been identified in rice (Oryza sativa). Previous studies have shown that stress conditions can induce their overexpression, but the role of those globins is still unclear. To better understand the functions of nsHb, the reactivity of rice Hb1 toward hydrogen peroxide (H₂O₂) has been studied in vitro. Our results show that recombinant rice Hb1 dimerizes through dityrosine cross-links in the presence of H₂O₂. By site-directed mutagenesis, we suggest that tyrosine 112 located in the FG loop is involved in this dimerization. Interestingly, this residue is not conserved in the sequence of the five rice non-symbiotic hemoglobins. Stopped-flow spectrophotometric experiments have been performed to measure the catalytic constants of rice Hb and its variants using the oxidation of guaiacol. We have shown that Tyrosine112 is a residue that enhances the peroxidase activity of rice Hb1, since its replacement by an alananine leads to a decrease of guaiacol oxidation. In contrast, tyrosine 151, a conserved residue which is buried inside the heme pocket, reduces the protein reactivity. Indeed, the variant Tyr151Ala exhibits a higher peroxidase activity than the wild type. Interestingly, this residue affects the heme coordination and the replacement of the tyrosine by an alanine leads to the loss of the distal ligand. Therefore, even if the amino acid at position 151 does not participate to the formation of the dimer, this residue modulates the peroxidase activity and plays a role in the hexacoordinated state of the heme.

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A series of novel Ga(III)—pyridine carboxylates ([Ga(Pic)₃]·H₂O (GaPic; HPic = picolinic acid), H₃O[Ga(Dpic)₂]·H₂O (GaDpic; H₂Dpic = dipicolinic acid), [Ga(Chel)(H₂O)(OH)]₂·4H₂O (GaChel; H₂Chel = chelidamic acid) and [Ga(Cldpic)(H₂O)(OH)]₂ (GaCldpic; H₂Cldpic = 4-chlorodipicolinic acid)) have been synthesized by simple one-step procedure. Vibrational spectroscopy (mid-IR), elemental analysis, thermogravimetric analysis and X-ray diffraction confirmed complexes molecular structure, inter and intramolecular interactions and their influence to spectral and thermal properties. Moreover, complex species speciation was described in Ga(III)-HPic and Ga(III)-H₂Dpic systems by potentiometry and ¹H NMR spectroscopy and mononuclear complex species were determined; [Ga(Pic)₂]⁺ (logβ₀₂₁ = 16.23(6)), [Ga(Pic)₃] (logβ₀₃₁ = 20.86(2)), [Ga(Dpic)₂]⁻ (logβ₀₂₁ = 15.42(9)) and [Ga(Dpic)₂(OH)]²⁻ (logβ_-121 = 11.08(4)). To confirm the complexes stability in 1% DMSO (primary solvent for biological testing), timescale ¹H NMR spectra were measured (immediately after dissolution up to 96 h). Antimicrobial activity evaluated by IC₅₀ (0.05 mM) is significant for GaDpic and GaCldpic against difficult to treat and multi-resistant P. aeruginosa. On the other hand, the GaPic complex is most effective against Jurkat, MDA-MB-231 and A2058 cancer cell lines and significantly also decreases the HepG2 cancer cells viability at 75 and 100 μM concentrations in a relatively short time (up to 48 h). In addition, fluorescence measurements have been used to elucidate bovine serum albumin binding activity between ligands, Ga(III) complexes and bovine serum albumin.

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Hypochlorite is known to oxidatively degrade the corrin ring of cobalamin. Here, transient reaction intermediates are described in the reaction of aqua as well as of cyano-cobalamin with hypochlorite, using stopped-flow UV–vis kinetics. For aqua-cobalamin, the intermediate is assigned as arising from substitution of the aqua ligand with hypochlorite. For cyano-cobalamin, the intermediate is proposed to arise from substitution of the benzimidazole ligand trans to the cyanide. In both cases, the intermediates would feature a new Co(III)-OCl⁻bond—which is also supported by density functional theory (DFT) calculations.

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Cyanocobalamin (CNCbl), a medicinal form of vitamin B₁₂, is resistant to glutathione (GSH), and undergoes intracellular processing via reductive decyanation producing the Co(II)-form of Cbl (Cbl(II)) mediated by the CblC-protein. Alteration of the CblC-protein structure might inhibit CNCbl processing. Here, we showed that introducing a bromine atom to the C10-position of the CNCbl corrin ring facilitates its reaction with GSH leading to the formation of Cbl(II) and cyanide dissociation. In a neutral medium, the reaction between C10-Br-CNCbl and GSH proceeds via the complexation of the reactants further leading to dimethylbenzimidazole (DMBI) substitution and electron transfer from GSH to the Co(III)-ion. The reaction is accelerated upon the GSH thiol group deprotonation. The key factors explaining the higher reactivity of C10-Br-CNCbl compared with unmodified CNCbl towards GSH are increasing the electrode potential of CNCbl two-electron reduction upon meso-bromination and the substantial labilization of DMBI, which was shown by comparing their reactions with cyanide and the pK_a values of DMBI protonation (pK_{a base-off}). Aquacobalamin (H₂OCbl) brominated at the C10-position of the corrin reacts with GSH to give Cbl(II) via GSH complexation and subsequent reaction of this complex with a second GSH molecule, whereas unmodified H₂OCbl generates glutathionyl-Cbl, which is resistant to further reduction by GSH.

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Two arene ruthenium(II) complexes [η⁶-(C₆H₆)Ru(pprip)Cl]PF₆ (Ru1; pprip = 2-(3-phenyl-1H-pyrazol-4-yl)-imidazolo[4,5-f][1,10]phenanthroline) and [η⁶-(C₆H₆)Ru(H₂iiP)Cl]PF₆ (Ru2; H₂iiP = 2-(indole-3-yl)-imidazolo[4,5-f][1,10]phenanthroline) have been synthesized and characterized in this work. Binding properties of Ru1 and Ru2 with the triplex RNA poly(U)•poly(A)*poly(U) were investigated by spectrophotometry and spectrofluorometry as well as viscosimetry. Analysis of spectroscopic titrations and viscosity measurements show that the two complexes bind with the triplex through intercalation, while the binding affinity for Ru2 toward the triplex is stronger than that for Ru1. Melting experiments indicate that the stabilizing effects of Ru1 and Ru2 toward the triplex differ from each other. Under the conditions used herein, Ru1 only stabilizes the Hoogsteen base-paired strand (third strand) without affecting stabilization of the Watson–Crick base-paired strand (the template duplex) of the triplex, while Ru2 stabilizes both the template duplex and the third strand. Although the two complexes prefer to stabilizing the third strand rather than the template duplex, the third-strand stabilization effect of Ru2 is stronger than that of Ru1. The obtained results of this work reveal that the planarity of the intercalative ligands plays an important role in the triplex stabilization by arene Ru(II) complexes.

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A series of new ferrocenyl nitroheterocyclic sulfonylhydrazones (1a–4a and 1b–2b) were prepared by the reaction between formyl (R = H) or acetyl (R = CH₃) nitroheterocyclic precursors [4/5-NO₂(C₅H₂XCOR), where X = O, S)] and ferrocenyl tosyl hydrazine [(η⁵-C₅H₅)Fe(η⁵-C₅H₄SO₂-NH-NH₂)]. All compounds were characterized by conventional spectroscopic techniques. In the solid state, the molecular structures of compounds 1a, 2b, and 3a were determined by single-crystal X–ray diffraction. The compounds showed an E-configuration around the C=N moiety. Evaluation of trypanocidal activity, measured in vitro against the Trypanosoma cruzi and Trypanosoma brucei strains, indicated that all organometallic tosyl hydrazones displayed activity against both parasite species with a higher level of potency toward T. brucei than T. cruzi. Moreover, the biological evaluation showed that the 5-nitroheterocyclic derivatives were more efficient trypanocidal agents than their 4-nitroheterocyclic counterparts.

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The control of nutrient availability is an essential ecological function of the host organism in host-microbe systems. Although often overshadowed by macronutrients such as carbohydrates, micronutrient metals are known as key drivers of host-microbe interactions. The ways in which host organisms control nutrient metal availability are dictated by principles in bioinorganic chemistry. Here I ponder about the actions of metal-binding molecules from the host organism in controlling nutrient metal availability to the host microbiota. I hope that these musings will encourage new explorations into the fundamental roles of metals in the ecology of diverse host-microbe systems.

In the treatment of hormone-dependent cancers, aromatase inhibitors (AI) are receiving increased attention due to some undesirable effects such as the risk of endometrial cancer and thromboembolism of SERMs (selective estrogen receptor modulators). Letrozole is the most active AI with 99% aromatase inhibition. Unfortunately, this compound also exhibits some adverse effects such as hot flashes and fibromyalgias. Therefore, there is an urgent need to explore new types of AIs that retain the same—or even increased—antitumor ability. Inspired by the letrozole structure, a set of new derivatives has been synthesized that include a ferrocenyl moiety and different heterocycles. The derivative that contains a benzimidazole ring, namely compound 6, exhibits a higher aromatase inhibitory activity than letrozole and it also shows potent cytostatic behavior when compared to other well-established aromatase inhibitors, as demonstrated by dose–response, cell cycle, apoptosis and time course experiments. Furthermore, 6 promotes the inhibition of cell growth in both an aromatase-dependent and -independent fashion, as indicated by the study of A549 and MCF7 cell lines. Molecular docking and molecular dynamics calculations on the interaction of 6 or letrozole with the aromatase binding site revealed that the ferrocene moiety increases the van der Waals and hydrophobic interactions, thus resulting in an increase in binding affinity. Furthermore, the iron atom of the ferrocene fragment can form a metal-acceptor interaction with a propionate fragment, and this results in a stronger coupling with the heme group—a possibility that is consistent with the strong aromatase inhibition of 6.

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Acylpyrazolone-based Schiff base ligands (HLⁿ) and their corresponding Pt(II) complexes with the general formula [Pt(Lⁿ)(Cl)] (n?=?1–3)?were synthesized and characterized by different spectroscopic techniques including ¹H-NMR, ¹⁹⁵Pt-NMR, LC-Mass, FT–IR, and UV–Vis spectroscopy, as well as elemental analysis. The crystal structure of one of the Schiff base ligands was also obtained. Based on the ADMET comparative results and the bioavailability radar charts, the complexes are completely drug-like. The Schiff base complexes with a structural difference of one methyl group in ligand were used as anticancer agents against human breast cancer cell lines SKBR3 and MDA-MB-231. The IC₅₀ values after treatment by [Pt(L¹)Cl] and [Pt(L²)Cl] were obtained more than cisplatin and less than carboplatin on cancer cells MDA-MB-231 and SKBR3, while the IC₅₀ value of [Pt(L³)Cl] was more than both other complexes and clinical Pt drugs. Molecular docking data showed that the groove binding is the main interaction with DNA double strands with a minor contribution from electrostatic interactions. To investigate the structure–activity relationship, DFT computational was done. All quantum chemical parameters display the drug approaching biomacromolecule and more biological activity of [Pt(L¹)Cl]?>?[Pt(L²)Cl]?>?[Pt(L³)Cl]. So, three Schiff base platinum complexes can be suitable candidates as anticancer drugs.

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Schiff-base ligands (HLn) and their Pt(II) complexes ([Pt(Ln)(Cl)], n=1-3) were obtained. To investigate their biological property and main interactions with DNA, ADMET, and cytotoxicity against MDA-MB-231 and SKBR3, DFT, and Molecular docking were done.

Two chiral ruthenium(II) polypyridyl complexes, Λ-[Ru(bpy)₂(dppx)]²⁺ (bpy?=?2,2′-bipyridine, dppx?=?7,8-dimethyldipyridophenazine; Λ-1) and Δ-[Ru(bpy)₂(dppx)]²⁺ (Δ-1) have been synthesized and characterized in this work. Interactions of Λ-1 and Δ-1 with the RNA triplex poly(U)?poly(A)*poly(U) have been investigated by various biophysical techniques. Spectrophotometric titrations and viscosity measurements suggested that enantiomers Λ-1 and Δ-1 bind with the triplex through intercalation, while the binding strengths of the two enantiomers toward the triplex differed only slightly from each other. Fluorescence titrations showed that although enantiomers Λ-1 and Δ-1 exhibited molecular “light switch” effects toward the triplex, the effect of Δ-1 was more marked. Furthermore, Furthermore, thermal denaturation showed that the two enantiomers have significantly different stabilizing effects on the triplex. The obtained results indicate that the racemic complex [Ru(bpy)₂(dppx)]²⁺ is similar to a non-specific metallointercalator for the triplex investigated in this study, and chiralities of Ru(II) polypyridine complexes have an important influence on the binding and stabilizing effects of enantiomers toward the triplex.

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Two chiral ruthenium(II) polypyridyl complexes, Λ-[Ru(bpy)₂(dppx)]²⁺ (bpy?=?2,2′-bipyridine, dppx?=?7,8-dimethyldipyridophenazine; Λ-1) and Δ-[Ru(bpy)₂(dppx)]²⁺ (Δ-1) have been synthesized and characterized in this work. Interactions of Λ-1 and Δ-1 with the RNA triplex poly(U)?poly(A)*poly(U) have been investigated by various biophysical techniques. The obtained results indicate that the racemic complex [Ru(bpy)₂(dppx)]²⁺ is similar as a non-specific metallointercalator for the triplex investigated in this study, and chiralities of Ru(II) polypyridine complexes have an important influence on the binding and stabilizing effects of enantiomers toward the triplex