Monoaryl derivatives as transthyretin fibril formation inhibitors: Design,synthesis, biological evaluation and structural analysis

Transthyretin (TTR) is a ß-sheet-rich homotetrameric protein that transports thyroxine (T4) and retinol both in plasma and in cerebrospinal fluid. TTR also interacts with amyloid-β, playing a protective role in Alzheimer’s disease. Dissociation of the native transthyretin (TTR) tetramer is widely accepted as the critical step in TTR amyloids fibrillogenesis, and is responsible for extracellular deposition of amyloid fibrils. Small molecules, able to bind in T4 binding sites and stabilize the TTR tetramer, are interesting tools to treat and prevent systemic ATTR amyloidosis. We report here the synthesis, in vitro evaluation and three-dimensional crystallographic analyses of new monoaryl-derivatives in complex with TTR. Of the derivatives reported here, the best inhibitor of TTR fibrillogenesis, 1d, exhibits an activity similar to diflunisal.     

Using Integrative Modeling Platform to compute,validate, and archive a model of a protein complex structure

Biology is advanced by producing structural models of biological systems, such as protein complexes. Some systems are recalcitrant to traditional structure determination methods. In such cases, it may still be possible to produce useful models by integrative structure determination that depends on simultaneous use of multiple types of data. An ensemble of models that are sufficiently consistent with the data is produced by a structural sampling method guided by a data‐dependent scoring function. The variation in the ensemble of models quantified the uncertainty of the structure, generally resulting from the uncertainty in the input information and actual structural heterogeneity in the samples used to produce the data. Here, we describe how to generate, assess, and interpret ensembles of integrative structural models using our open source Integrative Modeling Platform program ( https://integrativemodeling.org ).     

A protective effect of curcumin on cardiovascular oxidative stress indicators in systemic inflammation induced by lipopolysaccharide in rats

ObjectiveInflammation has been considered as an important factor in cardiovascular diseases (CVD). Curcumin has been well known for its anti-inflammatory effects. In current research, protective effect of curcumin on cardiovascular oxidative stress indicators in systemic inflammation induced by lipopolysaccharide (LPS) was investigated in rats.Material and methodsThe animals were divided into five groups and received the treatments during two weeks [1]: Control in which vehicle was administered instead of curcumin and saline was injected instead of LPS [2], LPS group in which vehicle of curcumin plus LPS (1 mg/kg) was administered [3-5], curcumin groups in them three doses of curcumin (5, 10 and 15 mg/kg) before LPS were administered.ResultsAdministration of LPS was followed by an inflammation status presented by an increased level of white blood cells (WBC) (p < 0.001). An oxidative stress status was also occurred after LPS injection which was presented by an increased level of malondialdehyde (MDA) while, a decrease in thiols, superoxide dismutase (SOD) and catalase(CAT) in all heart, aorta and serum (p < 0.001). The results also showed that curcumin decreased WBC (doses: 10 and 15 mg/kg) (p < 0.001) accompanying with a decrease in MDA (P < 0.01 and P < 0.001). Curcumin also improved the thiols and the activities of SOD and catalase (P < 0.05, P < 0.01 and P < 0.001).ConclusionBased on our findings, curcumin can ameliorates oxidative stress and inflammation induced by LPS in rats to protect the cardiovascular system.     

Predictive markers of safety and immunogenicity of adjuvanted vaccines

Vaccination represents one of the greatest public health triumphs; in part due to the effect of adjuvants that have been included in vaccine preparations to boost the immune responses through different mechanisms. Although a variety of novel adjuvants have been under development, only a limited number have been approved by regulatory authorities for human vaccines. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference on the current state of the art in the adjuvant field. Held at the U.S. Pharmacopeial Convention (USP) in Rockville, Maryland, USA, from 18 to 19 April 2013 and organized by the International Association for Biologicals (IABS), the conference focused particularly on the future development of effective adjuvants and adjuvanted vaccines and on overcoming major hurdles, such as safety and immunogenicity assessment, as well as regulatory scrutiny. More information on the conference output can be found on the IABS website, http://www.iabs.org/.     

Microbial transformation of curcumin by Rhizopus chinensis

Abstract

Curcumin (1) is a potent antioxidant and antitumor natural product. In spite of its efficacy and safety, its clinical use is hindered mainly by poor water solubility and bioavailability. Structural modification to introduce hydrophilic functions is a promising approach to resolve this problem. In the present study we first found that curcumin could be efficiently converted into glucosides by filamentous fungi including Rhizopus chinensis IFFI 03043, Absidia coerulea AS 3.3389 and Cunninghamella elegans AS 3.1207. Curcumin 4′-O-β-d-glucoside (2), together with hexahydrocurcumin (3), was isolated from a preparative-scale biotransformation with R. chinensis IFFI 03043 and characterized fully by NMR and MS. A time-course study revealed that curcumin could be efficiently converted into curcumin 4′-O-β-d-glucoside within 8 h when administered at 0.05 mmol L^?1 and the productivity was 57%. Additionally, the biotransformation products of curcumin by different fungal strains were analyzed by LC/MS. At least 15 metabolites were detected, and the predominant biotransformation reaction was glucosylation. This study provides a simple, efficient and less expensive approach for the preparation of curcumin glucosides. The introduction of the glucosyl function might be able to enhance the bioavailability of curcumin.     

Antibacterial activity and spectral studies of trivalent chromium,manganese, iron macrocyclic complexes derived from oxalyldihydrazide and glyoxal

A new series of complexes is synthesized by template condensation of oxalyldihydrazide and glyoxal in methanolic medium in the presence of trivalent chromium, manganese and iron salts forming complexes of the type: [M(C₈H₈N₈O₄)X]X₂ where M = Cr(III), Mn(III), Fe(III) and X = Cl^{? 1}, , CH₃COO^{? 1}. The complexes have been characterized with the help of elemental analyses, conductance measurements, magnetic susceptibility measurements, electronic, NMR, infrared and far infrared spectral studies. On the basis of these studies, a five coordinate square pyramidal geometry for these complexes has been proposed. The biological activities of the metal complexes were tested in vitro against a number of pathogenic bacteria and some of the complexes exhibited remarkable antibacterial activities.     

Antibacterial and Antifugal Mono- and Di-substituted Symmetrical and Unsymmetrical Triazine-derived Schiff-bases and their Transition Metal Complexes

A new series of antibacterial and antifungal triazine-derived mono- and di-substituted (symmetrical and unsymmetrical) Schiff-bases and their cobalt(II), copper(II), nickel(II) and zinc(II) metal complexes have been synthesized and characterized by their elemental analyses, molar conductances, magnetic moments and IR and electronic spectral measurements. IR spectra indicated the ligands to act as tridentate towards divalent metal ions via a trazine-N, the azomethine-N and, indole-NH and deprotonated-O of salicylaldehyde. The magnetic moments and electronic spectral data suggest octahedral geometry for the Co(II), Ni(II) and Zn(II)complexes and square-pyramid for Cu(II) complexes. NMR spectral data of the ligands and their diamagnetic zinc(II) complexes well-define their proposed structures/geometries. Elemental analyses data of the ligands and metal complexes agree with their proposed structures/geometries. The synthesized ligands, along with their metal complexes were screened for their antibacterial activity against Escherichia coli, Bacillus subtillis, Shigella flexneri, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella typhi and for antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glaberata. The results of these studies show the metal complexes to be more antibacterial/antifungal against two or more species as compared to the uncomplexed Schiff-base ligands.     

Structure and biological properties of first row d-transition metal complexes with N-substituted sulfonamides

Cobalt (II), copper (II), nickel (II) and zinc (II) complexes with 2-hydroxy-1-naphthaldehyde derived N-substituted sulfonamides have been synthesized and the nature of bonding and structure of compounds have been deduced from physical, analytical and spectral (IR, ¹H NMR, ¹³C NMR, Mass and electronic) data. An octahedral geometry has been suggested for the complexes. Complexes along with the ligands were assessed for their antibacterial and antifungal activities on different species of pathogenic bacteria and fungi. The results revealed the ligands to possess moderate to significant antibacterial activity which was, in many cases, enhanced on chelation. Similar results were observed for antifungal activity. Brine shrimp bioassay was also carried out for in vitro cytotoxic properties against Artemia salina.     

Carbonic Anhydrase Inhibitors: Schiff's Bases of Aromatic and Heterocyclic Sulfonamides and their Metal Complexes

Schiff's bases were obtained from aromatic/heterocyclic sulfonamides and amino-sulfonamide derivatives, such as sulfanilamide, homosulfanilamide, 4-aminoethyl-benzenesulfonamide and 5-amino-1,3,4-thiadiazole-2-sulfonamide. Metal complexes of some of these Schiff's bases, incorporating Zn(II), Co(II), Ni(II) and Cu(II) ions, were also prepared and tested as inhibitors of the zinc enzyme carbonic anhydrase (CA), and more specifically the red blood cell isozymes I and II. The Schiff's bases behaved as medium potency CA I and CA II inhibitors, whereas their metal complexes showed a highly enhanced potency, with several low nanomolar CA II inhibitors detected.