Cephalosporin-NO-donor prodrug PYRRO-C3D shows β-lactam-mediated activity against Streptococcus pneumoniae biofilms

Bacterial biofilms show high tolerance towards antibiotics and are a significant problem in clinical settings where they are a primary cause of chronic infections. Novel therapeutic strategies are needed to improve anti-biofilm efficacy and support reduction in antibiotic use. Treatment with exogenous nitric oxide (NO) has been shown to modulate bacterial signaling and metabolic processes that render biofilms more susceptible to antibiotics. We previously reported on cephalosporin-3\u27-diazeniumdiolates (C3Ds) as NO-donor prodrugs designed to selectively deliver NO to bacterial infection sites following reaction with β-lactamases. With structures based on cephalosporins, C3Ds could, in principal, also be triggered to release NO following β-lactam cleavage mediated by transpeptidases/penicillin-binding proteins (PBPs), the antibacterial target of cephalosporin antibiotics. Transpeptidase-reactive C3Ds could potentially show both NO-mediated anti-biofilm properties and intrinsic (β-lactam-mediated) antibacterial effects. This dual-activity concept was explored using Streptococcus pneumoniae, a species that lacks β-lactamases but relies on transpeptidases for cell-wall synthesis. Treatment with PYRRO-C3D (a representative C3D containing the diazeniumdiolate NO donor PYRRO-NO) was found to significantly reduce viability of planktonic and biofilm pneumococci, demonstrating that C3Ds can elicit direct, cephalosporin-like antibacterial activity in the absence of β-lactamases. While NO release from PYRRO-C3D in the presence of pneumococci was confirmed, the anti-pneumococcal action of the compound was shown to arise exclusively from the β-lactam component and not through NO-mediated effects. The compound showed similar potency to amoxicillin against S. pneumoniae biofilms and greater efficacy than azithromycin, highlighting the potential of C3Ds as new agents for treating pneumococcal infections

The design and synthesis of novel anti-malarial agents

A new convergent methodology has been developed for the synthesis of the anti-malarial lead compound ADAM (24). A series of 41 derivatives were successfully synthesized, 35 of which were new compounds; all of which related to ADAM (24). All the synthesized derivatives were screened against in vitro Plasmodium falciparum K1, of which 11 showed significant activity in the low micromolar range, including compound (46) (IC50 0.3 ?g/ml), (80) (0.7 ?g/ml). and (88) (1.4 ?g/ml). A preliminary structure activity relationship analysis study was performed, which suggested that while 4,6-diaminopyrimidine analogs are inactive, if one of the two amines are alkylated then anti-malarial activity is returned. In order to generate a more thorough analysis, more compounds need to be synthesized by modifying the side chain. The SAR study also suggests that the heteroatom nitrogens in the pyrimidine ring are required for anti-malarial activity. The entire range of derivatives based on 5-benzoyl-4,6-dichloropyrimidine are inactive. The replacement of the phenyl substituent with an isopropyl group resulted in good anti-malarial activity but less than the parent compound. Novel synthetic dimerising methodology mediated by thallium(III) trifluoroacetate has been developed for the synthesis of biindoles. The methodology included the development of 2,2- and 2,7-biindoles, and 2,7,7,7-triindole. A series of 41 new indole derivatives were synthesized and screened for anti-malarial activity, of which three showed significant anti-malarial activity. During this study, the dimerisation of indole mediated by triflic anhydride was demonstrated for the first time. There are two other interesting synthetic results were observed, the triflic anhydride-mediated bi-pyrroloindole formation and the formation of the 1,2-dihydropyridineindole. Most compounds synthesized here were further tested in a series of additional biological assays, and a number of them showed activity against HIV reverse transcriptase, integrase, tuberculosis, anti-fungal and anti-cancer. In particular, the biaryl derivatives showed moderate activity against tuberculosis and fungal, which may be able to investigate further. A couple of biaryl compounds also showed significant anti-cancer activity. [Note: this abstract contained scientific formulae that would not come across on this form. Please see the 01Front files abstract for the full details.

Dependence of organic interlayer diffusion on glass-transition temperature in OLEDs

Organic light-emitting diodes (OLEDs) are subject to thermal stress from Joule heating and the external environment. In this work, neutron reflectometry (NR) was used to probe the effect of heat on the morphology of thin three-layer organic films comprising materials typically found in OLEDs. It was found that layers within the films began to mix when heated to approximately 20 °C above the glass-transition temperature (T) of the material with the lowest T. Diffusion occurred when the material with the lowest T formed a supercooled liquid, with the rates of interdiffusion of the materials depending on the relative T's. If the supercooled liquid formed at a temperature significantly lower than the T of the higher-T material in the adjacent layer, then pseudo-Fickian diffusion occurred. If the two T's were similar, then the two materials can interdiffuse at similar rates. The type and extent of diffusion observed can provide insight into and a partial explanation for the "burn in" often observed for OLEDs. Photoluminescence measurements performed simultaneously with the NR measurements showed that interdiffusion of the materials from the different layers had a strong effect on the emission of the film, with quenching generally observed. These results emphasize the importance of using thermally stable materials in OLED devices to avoid film morphology changes

Effects of MnDPDP andICRF-187 on Doxorubicin-Induced Cardiotoxicityand Anticancer Activity1

Oxidative stress participates in doxorubicin (Dx)–induced cardiotoxicity. The metal complex MnDPDP and its metaboliteMnPLED possess SOD-mimetic activity, DPDP and PLED have, in addition, high affinity for iron. Mice wereinjected intravenously with MnDPDP, DPDP, or dexrazoxane (ICRF-187). Thirty minutes later, mice were killed, theleft atria were hung in organ baths and electrically stimulated, saline or Dx was added, and the contractility wasmeasured for 60 minutes. In parallel experiments, 10 μM MnDPDP or MnPLED was added directly into the organbath. The effect of MnDPDP on antitumor activity of Dx against two human tumor xenografts (MX-1 and A2780)was investigated. The in vitro cytotoxic activity was studied by co-incubating A2780 cells with MnDPDP, DPDP,and/or Dx. Dx caused a marked reduction in contractile force. In vivo treatment with MnDPDP and ICRF-187 attenuatedthe negative effect of Dx. When added directly into the bath, MnDPDP did not protect, whereas MnPLEDattenuated the Dx effect by approximately 50%. MnDPDP or ICRF-187 did not interfere negatively with the antitumoractivity of Dx, either in vivo or in vitro. Micromolar concentrations of DPDP but not MnDPDP displayed anin vitro cytotoxic activity against A2780 cells. The present results show that MnDPDP, after being metabolized toMnPLED, protects against acute Dx cardiotoxicity. Both in vivo and in vitro experiments show that cardioprotectiontakes place without interfering negatively with the anticancer activity of Dx. Furthermore, the results suggest thatthe previously described cytotoxic in vivo activity of MnDPDP is an inherent property of DPDP. Translational Oncology (2012) 5, 252–259funding agencies|Medical Research Council of Southeast Sweden|FORSS-85191|PledPharma AB||</p

Using SANS with Contrast-Matched Lipid Bicontinuous Cubic Phases To Determine the Location of Encapsulated Peptides, Proteins, and Other Biomolecules

An understanding of the location of peptides, proteins, and other biomolecules within the bicontinuous cubic phase is crucial for understanding and evolving biological and biomedical applications of these hybrid biomolecule–lipid materials, including during in meso crystallization and drug delivery. While theoretical modeling has indicated that proteins and additive lipids might phase separate locally and adopt a preferred location in the cubic phase, this has never been experimentally confirmed. We have demonstrated that perfectly contrast-matched cubic phases in D₂O can be studied using small-angle neutron scattering by mixing fully deuterated and hydrogenated lipid at an appropriate ratio. The model transmembrane peptide WALP21 showed no preferential location in the membrane of the diamond cubic phase of phytanoyl monoethanolamide and was not incorporated in the gyroid cubic phase. While deuteration had a small effect on the phase behavior of the cubic phase forming lipids, the changes did not significantly affect our results