Pyranmycins,a novel class of aminoglycosides with improved acid stability: the SAR of D-pyranoses on ring III of pyranmycin

[reaction: see text] The synthesis of a novel class of aminoglycosides, pyranmycins, is reported along with the structure activity relationship (SAR) of their antibacterial activity against Escherichia coli. Two pyranmycins show prominent activity (9 microM). Pyranmycins also manifest superior stability in acidic media. The SAR information will lead to the future designs of pyranmycin against drug resistant bacteria.     

Molecular docking and 3D-QSAR study of pyranmycin derivatives against 16S rRNA A site

To understand pharmacophore properties of pyranmycin derivatives and to design novel inhibitors of 16S rRNA A site, comparative molecular field analysis (CoMFA) approach was applied to analyze three-dimensional quantitative structure–activity relationship (3D-QSAR) of 17 compounds. AutoDock 3.0.5 program was employed to locate the orientations and conformations of the inhibitors interacting with 16S rRNA A site. The interaction mode was demonstrated in the aspects of inhibitor conformation, hydrogen bonding and electrostatic interaction. Similar binding conformations of these inhibitors and good correlations between the calculated binding free energies and experimental biological activities suggest that the binding conformations of these inhibitors derived from docking procedure were reasonable. Robust and predictive 3D-QSAR model was obtained by CoMFA with q² values of 0.723 and 0.993 for cross-validated and non-cross-validated, respectively. The 3D-QSAR model built here will provide clear guidelines for novel inhibitors design based on the Pyranmycin derivatives against 16S rRNA A site.     

Exploring the optimal site for modifications of pyranmycins with the extended arm approach

[reaction: see text] Continuing from the syntheses and the antibacterial studies of a library of pyranmycins, we further probed the proximity around ring III of pyranmycin by introducing an "extended arm" that has hydroxyethyl or aminoethyl groups at the O-2' ', O-3' ', or O-4' ' positions. The results from the antibacterial studies reveal the optimal structural motif is the attachment of an extended arm with a terminal hydroxyl group at the O-3' ' position.     

Antibacterial activity of two chalcones, xanthoangelol and 4-hydroxyderricin, isolated from the root of Angelica keiskei KOIDZUMI

Two chalcones, xanthoangelol (I) and 4-hydroxyderricin (II), isolated from the root of Angelica keiskei KOIDZUMI (Umbelliferae) showed antibacterial activity against gram-positive pathogenic bacteria. The activity of I on Micrococcus luteus IFO-12708 (minimum inhibitory concentration (MIC), 0.76 microgram/ml) was the same potency as that of gentamicin, which is used as a standard. Although the activity of both chalcones on plant-pathogenic bacteria was lower than that of streptomycin sulfate, used as a positive control, they also exhibited growth-inhibitory effects. The antibacterial activity of I isolated from Angelica keiskei KOIDZUMI is being reported here for the first time. The growth-inhibitory effect of II on plant-pathogenic bacteria is also reported for the first time in this paper.     

Steric modifications tune the regioselectivity of the alkane oxidation catalyzed by non-heme iron complexes

Iron complexes with the tetradentate N-donor ligand N,N'-di(phenylmethyl)-N,N'-bis(2-pyridinylmethyl)-1,2-cyclohexanediamine (bbpc) are reported. Despite the benzyl groups present on the amines, the iron compounds catalyze the oxygenation of cyclohexane to an extent similar to those employing less sterically encumbered ligands. The catalytic activity is strongly dependent on the counterion, with the highest activity and the strongest preference for alkane hydroxylation correlating to the most weakly coordinating anion, SbF(6)(-). The selectivity for the alcohol product over the ketone is amplified when acetic acid is present as an additive. When hydrocarbon substrates with both secondary and tertiary carbons are oxidized by H(2)O(2), the catalyst directs oxidation toward the secondary carbons to a greater degree than other previously reported iron-containing homogeneous catalysts.     

Entropic and enthalpic components of catalysis in the mutase and lyase activities of Pseudomonas aeruginosa PchB

The isochorismate-pyruvate lyase from Pseudomonas aeruginosa (PchB) catalyzes two pericyclic reactions, demonstrating the eponymous activity and also chorismate mutase activity. The thermodynamic parameters for these enzyme-catalyzed activities, as well as the uncatalyzed isochorismate decomposition, are reported from temperature dependence of k(cat) and k(uncat) data. The entropic effects do not contribute to enzyme catalysis as expected from previously reported chorismate mutase data. Indeed, an entropic penalty for the enzyme-catalyzed mutase reaction (ΔS(++) = -12.1 ± 0.6 cal/(mol K)) is comparable to that of the previously reported uncatalyzed reaction, whereas that of the enzyme-catalyzed lyase reaction (ΔS(++) = -24.3 ± 0.2 cal/(mol K)) is larger than that of the uncatalyzed lyase reaction (-15.77 ± 0.02 cal/(mol K)) documented here. With the assumption that chemistry is rate-limiting, we propose that a reactive substrate conformation is formed upon loop closure of the active site and that ordering of the loop contributes to the entropic penalty for converting the enzyme substrate complex to the transition state.     

Towards the understanding of the activity of G9a inhibitors: an activity landscape and molecular modeling approach

In this work, we analyze the structure–activity relationships (SAR) of epigenetic inhibitors (lysine mimetics) against lysine methyltransferase (G9a or EHMT2) using a combined activity landscape, molecular docking and molecular dynamics approach. The study was based on a set of 251 G9a inhibitors with reported experimental activity. The activity landscape analysis rapidly led to the identification of activity cliffs, scaffolds hops and other active an inactive molecules with distinct SAR. Structure-based analysis of activity cliffs, scaffold hops and other selected active and inactive G9a inhibitors by means of docking followed by molecular dynamics simulations led to the identification of interactions with key residues involved in activity against G9a, for instance with ASP 1083, LEU 1086, ASP 1088, TYR 1154 and PHE 1158. The outcome of this work is expected to further advance the development of G9a inhibitors.

     

Experimental study and thermodynamic modelling of methane clathrate hydrate dissociation conditions in silica gel porous media in the presence of methanol aqueous solution

In this work, the phase equilibria of clathrate hydrates of methane in the presence of pure water and 0.035 mass fraction of methanol aqueous solution in confined silica gel pores with (10 and 15) nm mean diameters are measured and reported. A thermodynamic model is also developed for prediction of the obtained experimental hydrate dissociation data. The Valderrama–Patel–Teja (VPT-EoS) equation of state (EoS) accompanied with the non-density dependent (NDD) mixing rules coupled with a previously developed activity model are applied to evaluate the fugacity of the species present and the activity coefficient of water in methanol aqueous solution. Acceptable agreement between the reported data and the predicted results using the proposed model and an existing method reported in the literature demonstrates the reliability of the presented model.     

Composition and antimicrobial activity of the essential oil of Actinidia macrosperma from China

Actinidia macrosperma is a medicinal plant in China and has been well known for its attraction to cats and activities against leprosy and cancers. The compositions and the antimicrobial activity of its leaf oil were reported for the first time. The oil obtained by hydrodistillation and analyzed by GC and GC-MS, was characterized by the high content of monoterpenes. Linalool (48.14%) is the major component identified, followed by 1,2-dimethyl-lindoline (7.94%), linolenic acid methylester (6.57%) and (E)-phytol (5.29%). The antimicrobial activity of the oil was evaluated against four bacterial and three fungal species. The results showed that it exhibited a mild antibacterial activity against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), a significant activity against Gram-negative bacteria (Escherichia coli), and no activity on Pseudomonas aeruginosa. The test fungi were more sensitive to the oil, with a MIC range of 0.78-1.56 microL mL(-1) than bacteria in the range which were significantly higher from 0.78 to 25.50 microL mL(-1).     

On the formation of homo-aza-steroids and derivatives by beckmann rearrangement. Antitumor activity of stereoisomers homo-aza-steroidal esters

The Beckmann rearrangement of steroidal oximes is reported. Different methods of esterification of homo-aza-steroids with carboxylic derivatives of N,N-bis(2-chloroethyl)aniline are reported. The lipophilic nature of the steroidal hormones is the reason for searching compounds containing as the biological platform the steroid molecule and as the active moiety the alkylating agent, such as nitrogen mustards linked to the steroid with a stable bond or with an easily cleaved ester or ether molecule and different other active species, hopefully to transport and deliver the alkylating agent to the specific target tissue. The concept to design hybrid compounds containing as the biological platform steroidal lactams and as the alkylating congener carboxylic derivatives of N,N-bis(2-chloroethyl)aniline might form compounds with synergistic activity. The findings suggest that the conformation of the alkylating agent influences the anticancer activity, while the amide group of the lactam molecule is important for activity in L1210 leukemia. These hybrid compounds with a modified steroid as the biological platform furnish derivatives with advantages compared to the unmodified steroids with alkylating agents. Different methods of esterification of homo-aza-steroids with carboxylic derivatives of N,N-bis(2-chloro-ethyl)aniline are reported.     

Direct Electrochemical Reaction of Horseradish Peroxidase Immobilized on the Surface of Active Carbon Powders

It is reported for the first time that horseradish peroxidase (HRP) immobilized on the active carbon can undergo a direct quasi-reversible electrochemical reaction.In addition,the immobilized HRP showed the stable bioelectrocatalytic activity for the reduction of H2O2.     

Thermosonimetry of the NBS—ICTA temperature standards

Thermosonimetry (TS) curves for the NBS—ICTA recommended DTA temperature standards (NBS standard references materials 759 and 760) are reported. These materials generally show two regions of TS activity. The first (lower temperature) region is associated with a variety of processes such as fluid inclusion release, grain boundary motions and microcrack propagation, whereas the second (higher temperature) region is associated with the polymorphic transformations. Incorporation of a DTA specimen holder assembly into the TS equipment has provided evidence that the temperatures of the peak TS activity in the transformation regions correspond to the extrapolated onset temperatures of the DTA peaks, suggesting that the polymorphic transformations provide these crystals with mechanisms for relief of mechanical strain.     

Comparison of the biological properties of several marine sponge-derived sesquiterpenoid quinones

Eight naturally occurring marine-sponge derived sesquiterpenoid quinones were evaluated as potential inhibitors of pyruvate phosphate dikinase (PPDK), a C4 plant regulatory enzyme. Of these, the hydroxyquinones ilimaquinone, ethylsmenoquinone and smenoquinone inhibited PPDK activity with IC50's (reported with 95% confidence intervals) of 285.4 (256.4-317.7), 316.2 (279.2-358.1) and 556.0 (505.9-611.0) microM, respectively, as well as being phytotoxic to the C4 plant Digitaria ciliaris. The potential anti-inflammatory activity of these compounds, using bee venom phospholipase A2 (PLA2), was also evaluated. Ethylsmenoquinone, smenospongiarine, smenospongidine and ilimaquinone inhibited PLA2 activity (% inhibition of 73.2 +/- 4.8 at 269 microM, 61.5 +/- 6.1 at 242 microM, 41.0 +/- 0.6 at 224 microM and 36.4 +/- 8.2 at 279 microM, respectively). SAR analyses indicate that a hydroxyquinone functionality and a short, hydroxide/alkoxide side-chain atC-20 is preferred for inhibition of PPDK activity, and that a larger amine side-chain at C-20 is tolerated for PLA2 inhibitory activity.     

Exchange current density of the hydrogen oxidation reaction on Pt/C in polymer solid base electrolyte

The exchange current density of the hydrogen oxidation reaction (HOR) on platinum supported on carbon (Pt/C) has been widely studied for liquid base electrolyte (LBE), but has yet to be reported for a polymer solid base electrolyte (SBE). The goal of this study is to determine the exchange current density for the HOR on Pt/C in an SBE using a hydrogen pump and to compare it with those in LBE and a polymer solid acid electrolyte (SAE). We find that the HOR activity in the SBE is almost the same as in LBE, and is nearly two orders of magnitude lower than in SAE. The similar HOR activities on Pt/C in SBE and LBE suggest that previously reported exchange current densities measured in LBE accurately reflect Pt/C's activity for the HOR in SBE fuel cells even though the modes of ion conduction in liquid and solid polymer electrolytes are inherently different.     

Facile synthetic access to and biological evaluation of the macrocyclic core of apoptolidin

Oxidative cleavage of the C-20/C-21 bond in apoptolidin (1) provides two fragments of similar complexity, facilitating a divide-and-diversify strategy for the determination of the structural basis for apoptolidin's biological activity, the remarkably selective induction of apoptosis in sensitive cell lines. The ability of compounds derived from this cleavage to inhibit mitochondrial F(0)F(1)-ATPase is reported. [structure: see text]     

Composition and antimicrobial activity of the essential oil of Acronychia pedunculata (L.) Miq. from Vietnam

The chemical composition and the antimicrobial activity of the essential oil isolated from aerial parts of Acronychia pedunculata (L.) Miq. from Vietnam are reported. Analysis was carried out by GC (RI), GC-MS and 13C NMR. Thirty-four compounds were identified, accounting for 92.8% of the oil. The major constituents were alpha-pinene (57.4%) and (E)-beta-caryophyllene (13.6%). The essential oil of A. pedunculata was shown to possess a broad spectrum of antimicrobial activity against various bacteria, particularly Salmonella enterica and Staphylococcus epidermidis.     

Evaluation of Pseudomonas aeruginosa deacetylase LpxC inhibitory activity of dual PDE4-TNFalpha inhibitors: a multiscreening approach

In this study, we have focused on the implication of a multiscreening approach in the evaluation of Pseudomonas aeruginosa deacetylase LpxC inhibitory activity of dual PDE4-TNFalpha inhibitors. A genetic function approximation (GFA) directed quantitative structure-activity relationship (QSAR) model was developed for LpxC inhibition on the basis of reported biological activity (Kline and Andersen, J. Med. Chem. 2002, 45, 3112-3129). Subsequently, reported PDE4-TNFalpha inhibitors (Klienman and Campbell, J. Med. Chem. 1998, 41, 266-270) were screened using the QSAR model. Whereby, the compounds were predicted to have equipotent activity with the most potent compound in reported LpxC inhibitor series. A docking analysis of these compounds carried out on the LpxC homology model corroborated the initial results. The compounds were then validated using surface electronic properties analysis and subjected to an adsorption, distribution, metabolism, excretion, and toxicity filter. Taken together, a multiscreening strategy was used to validate potential leads for LpxC inhibition.     

A reassessment of mycophenolic acid as a lead compound for the development of inhibitors of chikungunya virus replication

Mycophenolic acid (MPA) has been previously reported as an inhibitor of the chikugunya virus (CHIKV) with an EC₅₀ value of 0.2 μM. We used MPA as a lead compound designing and synthesizing a series of isatins and benzolactones in a typical medicinal chemistry program. The synthesis and testing of 19 derivatives produced compounds with no desired activity which prompted us to retest the lead compound, MPA. We can reveal that MPA shows no anti-CHIKV activity and therefore needs to be reassessed as a lead compound for this target.     

New polydentate ligand and catalytic properties of the corresponding ruthenium complex during sulfoxidation and alkene epoxidation

Bis(diimine)-ruthenium complexes constitute a class of catalysts with good activity for oxidation reactions, such as sulfoxidation and epoxidation. The synthesis and the full characterization of a new ruthenium complex bearing an original pentadentate ligand (L5pyr for 2,6-bis-(6-ethyl-2,2'-bipyridyl)-pyridine) is reported. Comparison of its activity with regard to[Ru(bpy)2(CH3CN)2](2+) and [Ru(bpy)2(py)(CH3CN)](2+) during alkene and sulfide oxidation allowed us to conclude that the addition of a fifth pyridine ligand in the coordination sphere improves the efficiency of the catalyst. Moreover, under these oxidation conditions a hydroxylation of the ligand L5pyr led to a better activity than its analogue [Ru(bpy)2(py)(CH3CN)](2+), especially during epoxidation of alkenes by PhI(OAc)2.     

Useful methods for the synthesis of isopropylidenes and their chemoselective cleavage

A catalytic amount of phosphotungstic acid (PTA) has been found to be a very effective catalyst for isopropylidenation of 1,2-diols and their deprotection at room temperature. The ease of handling, cost and activity of the catalyst, good to excellent yields and chemoselectivity for deprotection are some of the highlights of the reported method.