Structural Rearrangement Followed by Entrapment of Subnanometer Building Blocks of Iron Oxyhydroxide in Aqueous Iron Chloride Solutions.

Iron oxyhydroxide, a natural nanophase of iron found in the environment, plays a crucial role in regulating surface and groundwater composition. Recent research proposes that within the nonclassical prenucleation cluster growth model, subnanometer-sized clusters (olation clusters/Fe13 δ-Keggin oxolation clusters) might act as the prenucleation clusters (PNCs) of ferrihydrite or iron oxyhydroxide solid phase. However, these clusters are difficult to characterize as they are only observable momentarily in low-pH, high-Fe concentration solutions before agglomerating into extended solids, keeping the controversy over the true nature of the PNCs alive. In this study, we introduce large quantities of zinc acetate salt (ZA) into iron chloride solutions at the olation-oxolation boundary (3.6 mM Fe3+ at pH ∼2.6). Remarkably, this manipulation is found to alter the structural arrangement of these subnanometer clusters before blocking them in isolation for hours, even at pH 6, where extended iron oxyhydroxide phases typically precipitate. On the other hand, controlled addition of ZA allows partial unblocking, leading to anisotropic agglomeration into cylindrical rod-like structures. Experimental techniques such as synchrotron-based small-angle X-ray scattering, X-ray absorption spectroscopy, high-resolution transmission electron microscopy (TEM), and cryo-TEM, along with density functional theory (DFT) calculations, reveal the nature of the structural rearrangement and the crucial role of Zn2+ ions in cluster stabilization.

Bergofungin D, a peptaibol template for the introduction of chemical modifications, synthesis of analogs and comparative studies of their structures.

Bergofungin D is a helical peptide of the peptaibol family consisting of 14 amino acids, six of which are the helix inducer aminoisobutyric acid (Aib). In the second third of the sequence, a hydroxyproline causes a bending of the helix and a disruption of the hydrogen bond network, and Aib7 is the only amino acid in this region involved in the hydrogen bond network. Therefore, modification of this residue can serve as a probe to monitor the effect of introducing amino acid substitutions on this more fragile helical turn. To validate this approach, we simplified the original bergofungin D by reducing the number of non-classical amino acids, replacing the (R)-isovaleric acid by its enantiomer or an Aib and the hydroxyproline with a proline, respectively, without affecting its secondary structure. Within the modified structure, we replaced Aib7-Aib8 by its 1,2,3-triazolodipeptide equivalent or Aib7 by a serine or a dehydrobutyrine. We have reported and analyzed five crystal structures, three of which are new, demonstrating the usefulness of the modified bergofungin D as a probe for monitoring the introduction of amino acid substitutions within a helical structure.

Curious Behavior of Fe3+-As3+ Chemical Interactions and Nucleation of Clusters in Aqueous Medium.

The simultaneous presence of Fe3+ and As3+ ions in groundwater (higher ppb or lower ppm level concentrations at circumneutral pH) as well as in acid mine drainages (AMDs)/industrial wastewater (up to few thousand ppm concentration at strongly acidic pH) are quite common. Therefore, understanding the chemical interactions prevalent between Fe3+ and As3+ ions in aqueous medium leading to nucleation of ionic clusters/solids, followed by aggregation and growth, is of great environmental significance. In the present work, we attempt to probe the nucleation process of Fe3+-As3+ clusters in solutions of various concentrations and pHs (from AMD to groundwater-like) using a combination of experimental and theoretical techniques. Interestingly, our study reveals nucleation of primary FeAs clusters in nearly all of them independent of concentration or pH. Theoretical studies employed density functional theory (DFT) to predict the primary clusters as stable Fe4As4 units. The surprising resemblance of these clusters with known Fe3+-As3+ minerals at the local level was observed experimentally, which provides an important clue about solid-phase growth from a range of Fe3+-As3+ solutions. Our experimental findings are further supported by a stepwise reaction mechanism established from detailed DFT studies.

Analyzing mechanisms of action of antimicrobial peptides on bacterial membranes requires multiple complimentary assays and different bacterial strains.

Antimicrobial peptides (AMPs) commonly target bacterial membranes and show broad-spectrum activity against microorganisms. In this research we used three AMPs (nisin, epilancin 15×, [R4L10]-teixobactin) and tested their membrane effects towards three strains (Staphylococcus simulans, Micrococcus flavus, Bacillus megaterium) in relation with their antibacterial activity. We describe fluorescence and luminescence-based assays to measure effects on membrane potential, intracellular pH, membrane permeabilization and intracellular ATP levels. The results show that our control peptide, nisin, performed mostly as expected in view of its targeted pore-forming activity, with fast killing kinetics that coincided with severe membrane permeabilization in all three strains. However, the mechanisms of action of both Epilancin 15× as well as [R4L10]-teixobactin appeared to depend strongly on the bacterium tested. In certain specific combinations of assay, peptide and bacterium, deviations from the general picture were observed. This was even the case for nisin, indicating the importance of using multiple assays and bacteria for mode of action studies to be able to draw proper conclusions on the mode of action of AMPs.

Ruthenium pincer complexes for light activated toxicity: Lipophilic groups enhance toxicity.

Nine ruthenium CNC pincer complexes (1-9) were tested for anticancer activity in cell culture under both dark and light conditions. These complexes included varied CNC pincer ligands including OH, OMe, or Me substituents on the pyridyl ring and wingtip N-heterocyclic carbene (NHC) groups which varied as methyl (Me), phenyl (Ph), mesityl (Mes), and 2,6-diisopropylphenyl (Dipp). The supporting ligands included acetonitrile, Cl, and 2,2'-bipyridine (bpy) donors. The synthesis of complexes 8 and 9 is described herein and are fully characterized by spectroscopic (1H NMR, IR, UV-Vis, MS) and analytical techniques. Single crystal X-ray diffraction results are reported herein for 8 and 9. The other complexes (1-7) are reported elsewhere. The four most lipophilic ruthenium complexes (6, 7, 8, and 9) showed the best activity vs. MCF7 cancer cells with complexes 6 and 9 showing cytotoxicity and complex 7 and 8 showing light activated photocytotoxicity. The distribution of these compounds between octanol and water is reported as log(Do/w) values, and increasing log(Do/w) values correlate roughly with improved activity vs. cancer cells. Overall, lipophilic wingtip groups (e.g. Ph, Mes, Dipp) on the NHC ring and a lower cationic charge (1+ vs. 2+) appears to be beneficial for improved anticancer activity.

Thirtieth Anniversary of the Discovery of Laxaphycins. Intriguing Peptides Keeping a Part of Their Mystery.

Lipopeptides are a class of compounds generally produced by microorganisms through hybrid biosynthetic pathways involving non-ribosomal peptide synthase and a polyketyl synthase. Cyanobacterial-produced laxaphycins are examples of this family of compounds that have expanded over the past three decades. These compounds benefit from technological advances helping in their synthesis and characterization, as well as in deciphering their biosynthesis. The present article attempts to summarize most of the articles that have been published on laxaphycins. The current knowledge on the ecological role of these complex sets of compounds will also be examined.

Mode of action of teixobactins in cellular membranes.

The natural antibiotic teixobactin kills pathogenic bacteria without detectable resistance. The difficult synthesis and unfavourable solubility of teixobactin require modifications, yet insufficient knowledge on its binding mode impedes the hunt for superior analogues. Thus far, teixobactins are assumed to kill bacteria by binding to cognate cell wall precursors (Lipid II and III). Here we present the binding mode of teixobactins in cellular membranes using solid-state NMR, microscopy, and affinity assays. We solve the structure of the complex formed by an improved teixobactin-analogue and Lipid II and reveal how teixobactins recognize a broad spectrum of targets. Unexpectedly, we find that teixobactins only weakly bind to Lipid II in cellular membranes, implying the direct interaction with cell wall precursors is not the sole killing mechanism. Our data suggest an additional mechanism affords the excellent activity of teixobactins, which can block the cell wall biosynthesis by capturing precursors in massive clusters on membranes.

Highly Active Ruthenium CNC Pincer Photocatalysts for Visible-Light-Driven Carbon Dioxide Reduction.

Five ruthenium catalysts described herein facilitate self-sensitized carbon dioxide reduction to form carbon monoxide with a ruthenium catalytic center. These catalysts include four new and one previously reported CNC pincer complexes featuring a pyridinol derived N-donor and N-heterocyclic carbene (NHC) C-donors derived from imidazole or benzimidazole. The complexes have been characterized fully by spectroscopic and analytic methods, including X-ray crystallography. Introduction of a 2,2'-bipyridine (bipy) coligand and phenyl groups on the NHC ligand was necessary for rapid catalysis. [(CNC)Ru(bipy)(CH3CN)](OTf)2 is among the most active and durable photocatalysts in the literature for CO2 reduction without an external photosensitizer. The role of the structure of this complex in catalysis is discussed, including the importance of the pincer's phenyl wingtips, the bipyridyl ligand, and a weakly coordinating monodentate ligand.

Peptaibols as a model for the insertions of chemical modifications.

Peptaibols are linear non ribosomal peptides which have been the object of intense research efforts regarding their synthesis and the elucidation of the mechanism allowing their insertion in biological membranes. Forty years after their discovery they are still considered as model compounds and suitable probes for the investigation of new approaches aiming to test the efficacy of new coupling reagents, to physically and spectroscopically investigate the way by which they interact with the lipid bilayer and to develop artificial membrane pores. The stable helical secondary structure adopted by the peptaibols turn to be an adequate platform for gaining insight on the structural modifications induced by the substitution of the amide bond by 1,2,3-triazoles, but also for monitoring the impact of newly designed α,α-dialkyl glycine with fluorinated and silylated side chains as 2-aminoisobutyric acid mimic. Peptaibols secondary structure dictated by Aib high content has inspired the development of foldamers. Challenges and investigations on the above mentioned topics are discussed in this brief review.

How are 1,2,3-triazoles accommodated in helical secondary structures?

1,4-Disubstituted-1,2,3-triazole (Tz) is widely used in peptides as a trans-amide bond mimic, despite having hazardous effects on the native peptide activity. The impact of amide bond substitution by Tz on peptide secondary structures is scarcely documented. We performed a Tz scan, by systematically replacing peptide bonds following the Aib residues with Tz on two model peptaibols: alamethicin F50/5 and bergofungin D, which adopt stable α- and 310 helices, respectively. We observed that the Tz insertion, whatever its position in the peptide sequences, abolished their antimicrobial activity. The structural consequences of this insertion were further investigated using CD, NMR and X-ray diffraction. Importantly, five crystal structures that were incorporated with Tz were solved, showing various degrees of alteration of the helical structures, from minor structural perturbation of the helix to partial disorder. Together, these results showed that Tz insertions impair helical secondary structures.

Enhancing the Antimicrobial Activity of Alamethicin F50/5 by Incorporating N-terminal Hydrophobic Triazole Substituents.

A simple and efficient strategy is proposed to significantly improve the antibacterial activity of peptaibols and other antimicrobial peptides by N-terminal capping with 1,2,3-triazole bearing various hydrophobic substituents on C-4. Such N-terminal insertions on alamethicin F50/5 could enhance its antimicrobial activity on Gram-positive bacteria without modification of its overall three-dimensional structure. Although the native peptide and its analogues shared comparable helical contents, the crystal structure of one of the most active derivative showed a local slight distortion of the N-terminal extremity, which was also observed in solution using NMR spectroscopy. Importantly, fluorescence studies showed that the N-capped derivatives had increased affinity for liposomes, which may indicate they interacted more strongly with the bacterial membrane than alamethicin F50/5.

Straightforward strategy to substitute amide bonds by 1,2,3-triazoles in peptaibols analogs using Aibψ[Tz]-Xaa dipeptides.

Structured peptides gained more attention over a decade because of their biological properties, biocompatibility and ability to act as modulators of protein/protein interactions, antibiotics, analgesics, immunosuppressants or as imaging agents to cite a few relevant applications. However, their poor bioavalability due in part to the susceptibility of the peptide bond to proteolytic cleavages often impaired their development and considerably limited their therapeutic use. To circumvent these problems, many efforts are undertaken to discover stable amide bond mimics resistant to proteolytic degradation. Among them the 1,2,3-triazole emerged as a highly stable analogue of the trans-peptide bond to generate bioactive peptides. Here we report a convenient approach to readily substitute amide bonds by triazole rings in Aib-containing peptides using Aibψ[Tz]-Xaa dipeptide-like units. We defined their application in solid phase synthesis and generated short model peptide sequences to study the impact of the triazole incorporation on their conformations in solution by circular dichroism and nuclear magnetic resonance spectroscopies.

Arsenic induced myocardial toxicity in rats: alleviative effect of Trichosanthes dioica fruit.

The present study investigated the alleviative effect of aqueous extract of Trichosanthes dioica fruit (AQTD) against arsenic induced cardiotoxicity in Wistar albino rats. AQTD (50 and 100 mg/kg) was administered orally to rats for 20 consecutive days before oral administration of sodium arsenite (10 mg/kg) for 8 days. Then the body weights, heart weights, hematological profile, serum biochemical profile; myocardial antioxidative parameters viz. lipid peroxidation, reduced and oxidized glutathione, glutathione-S-transferase, glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and DNA fragmentation were evaluated. Pretreatment with AQTD markedly and significantly normalized body weights, heart weights, hematological profile, serum biochemical profile and significantly modulated all the myocardial antioxidative parameters and reduced DNA fragmentation in arsenic intoxicated rats. Therefore, T. dioica fruit possessed remarkable alleviative effects against arsenic induced myocardial toxicity in Wistar albino rats mediated by amelioration of arsenic induced myocardial oxidative stress by several mechanisms.

Amino acid chirons: a tool for asymmetric synthesis of heterocycles.

As a result of their easy availability in enantiomerically enriched form and their possession of synthetically transformable diverse functional groups, amino acids have been extensively used by synthetic organic and medicinal chemists as a chiral pool for access to heterocycles (monocycles, bicycles or polycycles, either bridged or fused). This review describes the syntheses of diverse asymmetric heterocycles with various membered rings (n = 3-9) followed by benzo or heteroannulated ones, for the period from 1996 to Dec. 2013. It details solution phase synthetic methodologies in which the naturally occurring α-amino acid is incorporated, totally or partially, into the final product.

Rationalized design, synthesis and pharmacological screening of amino acid linked spiro pyrrolidino oxyindole analogs through environment friendly reaction.

INTRODUCTION: The development of newer synthetic approaches toward the synthesis of polynuclear heteroaromatics and their application in the synthesis of some biologically active compounds has been discussed in this study. MATERIALS AND METHODS: The synthesis of novel spiro pyrrolidino oxindoles was performed for the construction of amino acid linked polynuclear heteroaromatics by cycloaddition reaction. This reaction method is one of the most important methods for the construction of spiro pyrrolidino oxindole from the commercially available starting material isatin. Then the synthesized compounds were subjected for evaluation of nitric oxide scavenging and cytotoxic effects against tumor cell lines. RESULTS: All the six synthesized compounds demonstrated promising antioxidant and cytotoxic effects in vitro. CONCLUSION: Form the present study, it can be concluded that the synthesized compounds are fruitful in terms of their chemical purity, structural novelty, marked biological activities (antioxidant and cytotoxic) in vitro and last of all the lucid and picturesque synthetic methodology to synthesize the molecules in a in a non-hazardous and environmental friendly way.

Aryl aryl methyl thio arenes prevent multidrug-resistant malaria in mouse by promoting oxidative stress in parasites.

We have synthesized a new series of aryl aryl methyl thio arenes (AAMTAs) and evaluated antimalarial activity in vitro and in vivo against drug-resistant malaria. These compounds interact with free heme, inhibit hemozoin formation, and prevent Plasmodium falciparum growth in vitro in a concentration-dependent manner. These compounds concentration dependently promote oxidative stress in Plasmodium falciparum as evident from the generation of intraparasitic oxidants, protein carbonyls, and lipid peroxidation products. Furthermore, AAMTAs deplete intraparasite GSH levels, which is essential for antioxidant defense and survival during intraerythrocytic stages. These compounds displayed potent antimalarial activity not only in vitro but also in vivo against multidrug-resistant Plasmodium yoelii dose dependently in a mouse model. The mixtures of enantiomers of AAMTAs containing 3-pyridyl rings were found to be more efficient in providing antimalarial activity. Efforts have been made to synthesize achiral AAMTAs 17-23 and among them, compound 18 showed significant antimalarial activity in vivo.

Deciphering the Structural Requirements of Nucleoside Bisubstrate Analogues for Inhibition of MbtA in Mycobacterium tuberculosis: A FB-QSAR Study and Combinatorial Library Generation for Identifying Potential Hits.

The re-emergence of tuberculosis infections, which are resistant to conventional drug therapy, has steadily risen in the last decade. Inhibitors of aryl acid adenylating enzyme known as MbtA, involved in siderophore biosynthesis in Mycobacterium tuberculosis, are being explored as potential antitubercular agents. The ability to identify fragments that interact with a biological target is a key step in fragment based drug design (FBDD). To expand the boundaries of quantitative structure activity relationship (QSAR) paradigm, we have proposed a Fragment Based QSAR methodology, referred here in as FB-QSAR, for deciphering the structural requirements of a series of nucleoside bisubstrate analogs for inhibition of MbtA, a key enzyme involved in siderophore biosynthetic pathway. For the development of FB-QSAR models, statistical techniques such as stepwise multiple linear regression (SMLR), genetic function approximation (GFA) and GFAspline were used. The predictive ability of the generated models was validated using different statistical metrics, and similarity-based coverage estimation was carried out to define applicability boundaries. To aid the creation of novel antituberculosis compounds, a bioisosteric database was enumerated using the combichem approach endorsed mining in a lead-like chemical space. The generated library was screened using an integrated in-silico approach and potential hits identified.