Properties of 2-C-Methyl-D-Erythritol 2,4-Cyclopyrophosphate,an Intermediate in Nonmevalonate Isoprenoid Biosynthesis

Extraction and purification from the biomass of Corynebacterium ammoniagenes of 2-C-methyl-D-erythritol 2,4-cyclopyrophosphate (MEC) was associated with its spontaneous transformation into a number of derivatives (which was due to the pyrophosphate bond lability and the formation of complexes with metals). These derivatives included 1,2-cyclophospho-4-phosphate, 2,4-diphosphate, 2,3-cyclophosphate, 1,4-diphosphate, and 3,5-diphosphate (identified by ¹H, ³¹P, and ¹³C NMR spectroscopy) and accounted for about 10% of the MEC. When added to a solution of DNA in the presence of the Fenton reagent, MEC prevented DNA decomposition. In addition, MEC slowed down the interaction of the reagent with tempol radicals, which indicates that complexation of ferrous ions by MEC attenuates their ability to catalyze the formation of hydroxyl radicals from hydrogen peroxide. In the presence of 0.23 mM MEC, the rate of respiration of rat liver mitochondria increased by 1.8 times. At 0.1–1.0 mM, MEC activated in vitro proliferation of human Vgamma9 T cells. It is suggested that MEC acts as an endogenous stabilizing agent for bacterial cells subjected to oxidative stress and as an immunomodulator for eukaryotic hosts.     

Antitumor Activity of Selenium and Search Parameters for Its New Potentially Active Derivatives

Russian Journal of Bioorganic Chemistry - The trace element selenium is known to manifest antitumor activity. There is a relationship between the development of cancer and selenium content in food....     

Immunomodulatory properties of 2-C-methyl-D-erythritol-2,4-cyclopyrophosphate and search for its new derivatives]

A strong immunomodulatory effect of 2-C-methyl-D-erythritol-2,4-cyclopyrophosphate (MEC) responsible for the survival of bacteria was shown on isolated macrophages and in experimental infections in mice (typhoid and tularemia). Derivatives of MEC were found by 1H-NMR spectroscopy under stress conditions in colorless mutants of the bacteria and isolated to be subsequently purified and used for modulation of the immune system of animals.     

QSAR and Docking Studies on Capsazepine Derivatives for Immunomodulatory and Anti-Inflammatory Activity

Capsazepine, an antagonist of capsaicin, is discovered by the structure and activity relationship. In previous studies it has been found that capsazepine has potency for immunomodulation and anti-inflammatory activity and emerging as a favourable target in quest for efficacious and safe anti-inflammatory drug. Thus, a 2D quantitative structural activity relationship (QSAR) model against target tumor necrosis factor-α (TNF-α) was developed using multiple linear regression method (MLR) with good internal prediction (r² = 0.8779) and external prediction (r² _pred = 0.5865) using Discovery Studio v3.5 (Accelrys, USA). The predicted activity was further validated by in vitro experiment. Capsazepine was tested in lipopolysaccharide (LPS) induced inflammation in peritoneal mouse macrophages. Anti-inflammatory profile of capsazepine was assessed by its potency to inhibit the production of inflammatory mediator TNF-α. The in vitro experiment indicated that capsazepine is an efficient anti-inflammatory agent. Since, the developed QSAR model showed significant correlations between chemical structure and anti-inflammatory activity, it was successfully applied in the screening of forty-four virtual derivatives of capsazepine, which finally afforded six potent derivatives, CPZ-29, CPZ-30, CPZ-33, CPZ-34, CPZ-35 and CPZ-36. To gain more insights into the molecular mechanism of action of capsazepine and its derivatives, molecular docking and in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) studies were performed. The results of QSAR, molecular docking, in silico ADMET screening and in vitro experimental studies provide guideline and mechanistic scope for the identification of more potent anti-inflammatory & immunomodulatory drug.     

Synthesis and Antiviral Properties of New Cycloalkanol Derivatives of Guanine

Abstract

New conformationaly constrained cycloalkanol derivatives of guanine have been prepared as potential anti-herpetic agents. None of these compounds was found to inhibit HSV or CMV replication in cell culture but some of them show some antagonism or synergism towards acyclovir protecting effect.     

Properties of 2-C-methyl-D-erythritol 2,4-cyclopyrophosphate--an intermediate in the non-mevalonate isoprenoid biosynthesis

Extraction and purification from the biomass of Corynebacterium ammoniagenes of 2-C-methyl-D-erhythritol 2,4-cyclopyrophosphate (MEC) was associated with its spontaneous transformation into a number of derivatives (which was due to pyrophosphate bond lability and the formation of complexes with metals). These derivatives included 1,2-cyclophospho-4-phosphate, 2,4-diphosphate, 2,3-cyclophosphate, 1,4-diphosphate, and 3,5-diphosphate (identified by 1H, 31P, and 13C NMR spectroscopy) and accounted for about 10% MEC. When added to a solution of DNA in the presence of the Fenton reagent, MEC prevented DNA decomposition. In addition, MEC slowed down the interaction of the reagent with tempol radicals, which indicates that complexation of ferrous ions by MEC attenuates their ability to catalyze the formation of hydroxyl radicals from hydrogen peroxide. In the presence of 0.23 mM MEC, the rate of respiration of rat liver mitochondria increased 1.8 times. At 0.1-1.0 mM, MEC activated in vitro proliferation of human Vgamma9 T-cells. It is suggested that MEC acts as an endogenous stabilizing agent for bacterial cells subjected to oxidative stress and as an immunomodulator for eukaryotic hosts.     

The Search for New Amber Ingredients

There is a constant need for developing new fragrance ingredients in the flavor and fragrance industry, as it allows perfumers to create unique and differentiating perfumes for fine as well as functional products. Among all the categories of notes used in perfume creation, amber notes are indispensible and ubiquitous in their presence in all perfumes. Not only amber notes impart high performance and substantivity to fragrances, but they are paramount in the development of classic and legendary fragrances. This article is based on the plenary lecture delivered at the flavor & fragrance 2013 conference of the German Chemical Society in Leipzig, Germany. The strategy, rationale, and the various synthetic approaches that led to the discovery of two new very powerful, woody, amber materials, Amber Xtreme^® ( 1 ) and Trisamber^® ( 2 ), are delineated.     

Immunomodulatory Properties of Streptococcus and Veillonella Isolates from the Human Small Intestine Microbiota

The human small intestine is a key site for interactions between the intestinal microbiota and the mucosal immune system. Here we investigated the immunomodulatory properties of representative species of commonly dominant small-intestinal microbial communities, including six streptococcal strains (four Streptococcus salivarius, one S. equinus, one S. parasanguinis) one Veillonella parvula strain, one Enterococcus gallinarum strain, and Lactobacillus plantarum WCFS1 as a bench mark strain on human monocyte-derived dendritic cells. The different streptococci induced varying levels of the cytokines IL-8, TNF-α, and IL-12p70, while the V. parvula strain showed a strong capacity to induce IL-6. E. gallinarum strain was a potent inducer of cytokines and TLR2/6 signalling. As Streptococcus and Veillonella can potentially interact metabolically and frequently co-occur in ecosystems, immunomodulation by pair-wise combinations of strains were also tested for their combined immunomodulatory properties. Strain combinations induced cytokine responses in dendritic cells that differed from what might be expected on the basis of the results obtained with the individual strains. A combination of (some) streptococci with Veillonella appeared to negate IL-12p70 production, while augmenting IL-8, IL-6, IL-10, and TNF-α responses. This suggests that immunomodulation data obtained in vitro with individual strains are unlikely to adequately represent immune responses to mixtures of gut microbiota communities in vivo. Nevertheless, analysing the immune responses of strains representing the dominant species in the intestine may help to identify immunomodulatory mechanisms that influence immune homeostasis.     

New Synthetic Tools for Peptide-Tetraphenylporphyrin Derivatives

New metal-tetraphenylporphyrins and Fmoc-lysine-metalloporphyrin derivatives have been used to prepare peptide-porphyrin and peptide-metalloporphyrin compounds via solid-phase peptide synthesis. A water-soluble peptide, covalently bound to a manganese(III)-porphyrin, has been used as a catalyst to promote the oxidation of ABTS by hydrogen peroxide or t-butylhydroperoxide.     

Phenotypic and Immunomodulatory Properties of Equine Cord Blood-Derived Mesenchymal Stromal Cells

Multipotent mesenchymal stromal cells (MSC) have attracted interest for their cytotherapeutic potential, partly due to their immunomodulatory abilities. The aim of this study was to test the robustness of our equine cord blood (CB) MSC isolation protocol, to characterize the CB-MSC before and after cryopreservation, and to evaluate their immunosuppressive phenotype. We hypothesized that MSC can be consistently isolated from equine CB, have unique and reproducible marker expression and in vitro suppress lymphoproliferation. Preliminary investigation of constitutive cytoplasmic Toll-like receptor (TLR) 3 and 4 expression was also preformed due to their possible association with anti- or pro-inflammatory MSC phenotypes, respectively. Surface markers were assessed for antigen and mRNA expression by flow cytometry and quantitative polymerase chain reaction (qPCR). Immunomodulatory properties were evaluated in mixed lymphocyte reaction assays, and TLR3 and TLR4 expression were measured by qPCR and immunocytochemistry (ICC). CB-MSC were isolated from each off nine cord blood samples. CB-MSC highly expressed CD29, CD44, CD90, and lacked or had low expression of major histocompatibility complex (MHC) class I, MHC-II, CD4, CD8, CD11a/18 and CD73 before and after cryopreservation. CB-MSC suppressed in vitro lymphoproliferation and constitutively expressed TLR4. Our findings confirmed CB as a reliable MSC source, provides an association of surface marker phenotype and mRNA expression and suggest anti-inflammatory properties of CB-MSC. The relationship between TLRs and lymphocyte function warrants further investigation.     

Peroxidase-catalyzed Oxidation of 3,3",5,5"-Tetramethylbenzidine in the Presence of 2,4-Dinitrosoresorcinol and Polydisulfide Derivatives of Resorcinol and 2,4-Dinitrosoresorcinol

A comparative study of the kinetics of peroxidase-catalyzed oxidation of 3,3",5,5"-tetramethylbenzidine (TMB) in the presence of 2,4-dinitrosoresorcinol (DNR), its polydisulfide derivative [poly(DNRDS)], and resorcinol polydisulfide [poly(RDS)], substances that competitively inhibit the formation of TMB conversion product, was carried out. The inhibition constants K _i for DNR, poly(DNRDS), and poly(RSD) were determined at 20°C and pH 6.4 to be 110, 13.5, and 0.78 M, respectively. The stoichiometric coefficients of inhibition were calculated to be 0.38 and 76 for poly(DNRDS) and poly(RDS), respectively. In the pH range 6.4–7.0, the initial rates of the peroxidative oxidation of TMB, and its mixtures with DNR and poly(DNRDS) and the K _i value for poly(RDS) substantially decreased with increasing pH. The kinetic parameters of poly(RDS) (K _i 0.22–0.78 M and f 76) suggest that it is the most efficient inhibitor of peroxidase oxidation of TMB: in micromolar concentrations, it completely stops this process and can be used in EIA.     

New Synthetic Tools for Peptide-Tetraphenylporphyrin Derivatives

Summary New metal-tetraphenylporphyrins and Fmoc-lysine-metalloporphyrin derivatives have been used to prepare peptide-porphyrin and peptide-metalloporphyrin compounds via solid-phase peptide synthesis. A water-soluble peptide, covalently bound to a manganese(III)-porphyrin, has been used as a catalyst to promote the oxidation of ABTS by hydrogen peroxide ort-butylhydroperoxide.     

Proton NMR Spectra of 2,4-Dinitrophenyl Derivatives of Amino Acids

During the decay of wood by the typical white rot fungus Coriolus versicolor, Laccase III was the most abundantly secreted phenol oxidase. In this study, we proposed a possibility of the intermediate degradation steps of polymeric lignin by a purified Laccase III using synthetic [β-¹³C] and [β-¹⁴C]lignin (DHP). When the [β-¹⁴C]DHP was incubated with Laccase III, the water-soluble degradation product formed was about 8% of the applied [β-¹⁴C]DHP. The enzymic attack of Laccase III catalyzed the cleavage of the intermonomer linkages in the side chain structure of the polymeric lignin. In polymeric lignin metabolism by this fungus, laccase activity was closely related to the accumulation of water-soluble degradation products.     

Synthesis and Antioxidant Properties of Psoralen Derivatives

Five psoralen derivatives were synthesized and the structures of them were characterized by ¹H-NMR, ¹³C-NMR, and IR. The antioxidant properties of the compounds were tested by inhibiting the free radical-initiated DNA oxidation and scavenging the radical reaction. The results showed that the effective stoichiometric factors (n) of the compounds V and IV could reach 2.00 and 2.11 in the system of inhibiting the DNA oxidation reaction initiated by 2,2′-Azobis(2-methylpropionamidine) dihydrochloride (AAPH). In the inhibition of ⋅OH-oxidation of the DNA system, compounds I ~ V showed antioxidant properties. The thiobarbituric acid absorbance (TBARS) percentages of compounds IV and V were 76.19 % and 78.84 %. Compounds I ~ V could also inhibit Cu²⁺/GSH-oxidation of DNA, and all compounds exhibited good antioxidant properties except compound II (94.00 %). All the five compounds were able to trap diammonium 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonate) salt radical (ABTS⁺⋅), 2,2-diphenyl-1-picrylhydrazyl radical (DPPH⋅) and 2,6-di-tert-butyl-alpha-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-p-tolylox radical (galvinoxyl⋅). The ability of compounds I ~ V to scavenge those free radicals can be measured by the k values. The k values ranged from 0.07 to 0.82 in scavenging ABTS⁺⋅, galvinoxyl, and DPPH radicals, respectively.     

Synthesis and Properties of Novel NTP Derivatives

Abstract

Simple method for the preparation of anhydrides of nucleoside-5′-monophosphoric acid and with 1-hydroxyethane-1,1-diylbis(phosphonic acid) has been developed.     

Design,Synthesis, and Antitumor Activity of New N4-Alkyl-N2-Phenyl-Pyrrolo[3,2-d]Pyrimidine-2,4-Diamine Derivatives as CDK6 Inhibitors

Russian Journal of Bioorganic Chemistry - In this study, a series of new N4-alkyl-N2-phenyl-pyrrolo[3,2-d]pyrimidine-2,4-diamine derivatives has been designed and synthesized. The...