Mixing of peptides and electrophilic traps gives rise to potent, broad-spectrum proteasome inhibitors

The synthesis and evaluation of hybrid proteasome inhibitors that contain structural elements of the known inhibitors bortezomib, epoxomicin and peptide vinyl sulfones is described. From the panel of 15 inhibitors some structure activity relationships can be deduced with regard to inhibitory activity in relation to peptide recognition element, inhibitor size and nature of the electrophilic trap. Further, the panel contains one of the most potent peptide-based pan-proteasome inhibitors reported to date.     

Hydrogen-atom transfer in open-shell organometallic chemistry: the reactivity of Rh(II)(cod) and Ir(II)(cod) radicals

A series of new metalloradical rhodium and iridium complexes [M(II)(cod)(N-ligand)](2+) in the uncommon oxidation state +II were synthesized by one-electron oxidation of their [M(I)(cod)(N-ligand)](+) precursors (M=Rh, Ir; cod=(Z,Z)-1,5-cyclooctadiene; and N-ligand is a podal bis(pyridyl)amine ligand: N,N-bis(2-pyridylmethyl)amine (dpa), N-(2-pyridylmethyl)-N-(6-methyl-2-pyridylmethyl)amine (pla), or N-benzyl-N,N-bis(6-methyl-2-pyridylmethyl)amine (Bn-dla). EPR spectroscopy, X-ray diffraction, and DFT calculations reveal that each of these [M(II)(cod)(N-ligand)](2+) species adopts a square-pyramidal geometry with the two cod double bonds and the two pyridine fragments in the basal plane and the N(amine) donor at the apical position. The unpaired electron of these species mainly resides at the metal center, but the apical N(amine) donor also carries a considerable fraction of the total spin density (15-18 %). Density functional calculations proved a valuable tool for the analysis and simulation of the experimental EPR spectra. Whereas the M(II)(olefin) complexes are quite stable as solids, in solution they spontaneously transform into a 1:1 mixture of M(III)(allyl) species and protonated M(I)(olefin) complexes (in the forms [M(I)(olefin)(protonated N-ligand)](2+) for M=Rh and [M(III)(H)(olefin)(N-ligand)](2+) for M=Ir). Similar reactions were observed for the related propene complex [M(II)(propene)(Me(2)tpa)](2+) (Me(2)tpa=N,N,N-tris(6-methyl-2-pyridylmethyl)amine). The decomposition rate of the [M(II)(cod)(N-ligand)](2+) species decreases with increasing N-ligand bulk in the following order: dpa>pla>Bn-dla. Decomposition of the most hindered [M(II)(cod)(Bn-dla)](2+) complexes proceeds by a second-order process. The kinetic rate expression v=k(obs)[M(II)](2) in acetone with k(obs)=k'[H(+)][S], where [S] is the concentration of additional coordinating reagents (MeCN), is in agreement with ligand-assisted dissociation of one of the pyridine donors. Solvent coordination results in formation of more open, reactive species. Protonation of the noncoordinating pyridyl group increases the concentration of this species, and thus [H(+)] appears in the kinetic rate expression. The kinetic data are in agreement with bimolecular hydrogen-atom transfer from M(II)(cod) to another M(II) species (DeltaH( not equal)=11.5+/-2 kcal mol(-1), DeltaS( not equal)=-27+/-10 cal K(-1) mol(-1), and DeltaG( not equal)(298 K)=19.5+/-5 kcal mol(-1)).     

Protonation of a Biologically Relevant CuII μ‐Thiolate Complex: Ligand Dissociation or Formation of a Protonated CuI Disulfide Species?

The proton‐induced electron‐transfer reaction of a Cu^II μ‐thiolate complex to a Cu^I‐containing species has been investigated, both experimentally and computationally. The Cu^II μ‐thiolate complex [Cu^II₂( L^MeS )₂]²⁺ is isolated with the new pyridyl‐containing ligand L^MeSSL^Me , which can form both Cu^II thiolate and Cu^I disulfide complexes, depending on the solvent. Both the Cu^II and the Cu^I complexes show reactivity upon addition of protons. The multivalent tetranuclear complex [Cu^I₂Cu^II₂( LS )₂(CH₃CN)₆]⁴⁺ crystallizes after addition of two equivalents of strong acid to a solution containing the μ‐thiolate complex [Cu^II₂( LS )₂]²⁺ and is further analyzed in solution. This study shows that, upon addition of protons to the Cu^II thiolate compound, the ligand dissociates from the copper centers, in contrast to an earlier report describing redox isomerization to a Cu^I disulfide species that is protonated at the pyridyl moieties. Computational studies of the protonated Cu^II μ‐thiolate and Cu^I disulfide species with LSSL show that already upon addition of two equivalents of protons, ligand dissociation forming [Cu^I(CH₃CN)₄]⁺ and protonated ligand is energetically favored over conversion to a protonated Cu^I disulfide complex.     

Cholinergic Chemotransmission and Anesthetic Drug Effects at the Carotid Bodies

General anesthesia is obtained by administration of potent hypnotics, analgesics and muscle relaxants. Apart from their intended effects (loss of consciousness, pain relief and muscle relaxation), these agents profoundly affect the control of breathing, in part by an effect within the peripheral chemoreflex loop that originates at the carotid bodies. This review assesses the role of cholinergic chemotransmission in the peripheral chemoreflex loop and the mechanisms through which muscle relaxants and hypnotics interfere with peripheral chemosensitivity. Additionally, consequences for clinical practice are discussed.     

Broadening the absorption of conjugated polymers by "click" functionalization with phthalocyanines

Conjugated copolymer derivatives of poly[2-methoxy-5-(3',7'-dimethyloctyloxy)-1,4-phenylenevinylene] (MDMO-PPV) and poly(3-hexylthiophene) (P3HT) containing 10% of alkyne functionalities in the side chains have been prepared using the sulfinyl precursor route and the Rieke method, respectively. With the aim of expanding the absorption range of these conjugated polymers for their use in bulk heterojunction (BHJ) polymer:fullerene solar cells, appropriate phthalocyanine (Pc) molecules have been covalently bound through a post-polymerization "click chemistry" reaction between the alkyne functionalities in the side chains of the copolymers and a Pc functionalized with an azide moiety. The resulting poly(p-phenylenevinylene)-Pc (PPV-Pc) material holds a 9 mol% content of Pcs, while the polythiophene-Pc material (PT-Pc) contains a 8 mol% of Pc-functionalization in the side chains. As expected, the presence of the Pc contributes to the extension of the absorption up to 700 nm. BHJ solar cells have been prepared using PPV-Pc and PT-Pc materials in combination with PCBM. Although the Pc absorption contributes to the generation of photocurrent, the overall power conversion efficiencies (PCE) obtained from these cells are lower than those obtained with BHJ P3HT:PCBM (1:1) and MDMO-PPV:PCBM (1:4) solar cells. A plausible explanation could be the moderate solubility of the PPV-Pc and PT-Pc materials that limits the processing into thin films.     

Validation of automated library-based qualitative screening of pesticides by comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry

A method for automated detection and reporting of pesticides in plant materials based on comprehensive two-dimensional GC/time-of-flight MS with library-based detection by software has been developed and validated. Optimum settings for detection parameters such as spectral match threshold and first and second dimension retention time tolerances were assessed with respect to occurrence of false detects and false negatives. Next the method was validated following European Union guidelines established for qualitative screening of pesticides. The validation was largely done in retrospect by using data obtained for spiked samples (235 pesticides, various crops, 0.01-0.2 mg/kg) that had been analyzed previously with routine samples over a period of 18 months. At 0.01 mg/kg, the required 95% confidence level (<5% false negatives) was met for 83 compounds. This increased to 185 compounds at the 0.2 mg/kg level. For a number of pesticides, especially at low levels, it had to be concluded that at this stage the method was not fit-for-purpose to reliably demonstrate the absence of pesticides in samples to be analyzed. On the other hand, the fact that the overall detection rate at 0.01 mg/kg was 71% clearly showed that the method does provide added value for the numerous pesticides that are not covered by quantitative methods because the infrequent occurrence does not justify inclusion in such methods.