Antiviral efficacy against influenza virus and pharmacokinetic analysis of a novel MEK-inhibitor, ATR-002, in cell culture and in the mouse model.

Antiviral therapies against influenza are required, especially for high-risk patients, severe influenza and in case of highly pathogenic influenza virus (IV) strains. However, currently, licensed drugs that target the virus directly are not very effective and often lead to the development of resistant IV variants. This may be overcome by targeting host cell factors that are required for IV propagation. IV induces a variety of host cell signaling cascades, such as the Raf/MEK/ERK kinase pathway. The activation of this pathway is necessary for IV propagation. MEK-inhibitors block the activation of the pathway on the bottleneck of the signaling cascade leading to impaired virus propagation. In the present study, we aimed to compare the antiviral potency and bioavailability of the MEK-inhibitor CI-1040 versus its major active metabolite ATR-002, in vitro as well as in the mouse model. In cell culture assays, an approximately 10-fold higher concentration of ATR-002 is required to generate the same antiviral activity as for CI-1040. Interestingly, we observed that considerably lower concentrations of ATR-002 were required to achieve a reduction of the viral load in vivo. Pharmacokinetic studies with ATR-002 and CI-1040 in mice have found the Cmax and AUC to be far higher for ATR-002 than for CI-1040. Our results thereby demonstrate the in vivo superiority of the active metabolite ATR-002 over CI-1040 as an antiviral agent despite its weaker cell membrane permeability. Therefore, ATR-002 is an attractive candidate for development as an efficient antiviral agent, especially given the fact that a treatment based on cellular pathway inhibition would be far less likely to lead to viral drug resistance.

Collision-Induced Dissociation Ion Mobility Mass Spectrometry for the Elucidation of Unknown Structures in Strained Polycyclic Aromatic Hydrocarbon Macrocycles.

Structure determination of unexpected products obtained during synthesis of large carbon nanotube sidewall segments with more than 200 carbon atoms represents a challenging task for traditional analytical methods. Herein, we investigate a homologous series of four products having the same number of carbon atoms but slightly different hydrogen numbers ranging from 168 to 162. We demonstrate that the combination of mass spectrometry, ion mobility separation, and collision-induced dissociation (CID) can be used to finally elucidate the complete structures with high certainty. The postulated 1,2-phenyl shift as origin for the side reaction could be proven by changes in the minimum fragment sizes. A combination of CID and ion mobility spectrometry was applied for the first time to prove the cyclic nature of all molecules by the significant size increase upon ring opening. Thereby, also, more compact molecules were discovered in the gas phase with thus far unknown structures. Finally, the potential presence of numerous isomers could be ruled out by drift time measurements and molecular modeling together with theoretical collision cross-section (CCS) calculations. Surprisingly, only one defined structure could be assigned to each macrocycle in the homologous series, most likely as a result of natural selection rules driven by ring strain and steric hindrance. With a decreasing hydrogen content, the macrocycles undergo a stepwise transition from a cylindrical to conical shape. Overall, ion mobility mass spectrometry together with molecular modeling shows great potential to analyze unknown structures, especially in cases where structure determination by X-ray single-crystal analysis is not applicable.

The Precise Synthesis of Phenylene-Extended Cyclic Hexa-peri-hexabenzocoronenes from Polyarylated [n]Cycloparaphenylenes by the Scholl Reaction.

The longitudinal extension of cycloparaphenylenes (CPP) towards ultrashort carbon nanotubes (CNTs) is essential for the solution based bottom-up synthesis of CNTs. Herein, the longitudinal extension of the CPP skeleton by the introduction of hexaphenylbenzene units towards polyarylated [n]CPPs is described. Further, the applicability of the Scholl reaction to selectively form graphenic sidewalls is demonstrated. The ring size and substitution patterns of the polyarylated [n]CPPs were varied to overcome strain-induced side reactions during the oxidative cyclodehydrogenation and cyclic para-hexa-peri-hexabenzocoronene trimers ([3]CHBCs) were selectively obtained. This concept is envisioned as an access to ultrashort carbon nanotubes subject to the condition that further benzene rings with the right connectivity will be inserted.

π-extended [12]cycloparaphenylenes: from a hexaphenylbenzene cyclohexamer to its unexpected C2-symmetric congener.

The synthesis of π-extended [12]cycloparaphenylene (CPP) derivatives from a kinked triangular macrocycle is presented. Depending on the reaction conditions for reductive aromatization, either a hexaphenylbenzene cyclohexamer or its C2-symmetric congener was obtained. Their structures were confirmed by NMR spectroscopy or X-ray crystallographic analysis. With the support of DFT calculations, a mechanistic explanation for the unexpected formation of the oval shaped bis(cyclohexadiene)-bridged C2-symmetric macrocycle is provided. The here employed congested hexaphenylbenzene mode of connectivity in conjunction with a non-strained precursor improves oxidative cyclodehydrogenation toward the formation of ultrashort carbon nanotubes (CNT)s. Thus, this strategy can pave the way for new conceptual approaches of a solution-based bottom-up synthesis of CNTs.

Cobalt phenanthroline-indole macrocycles as highly active electrocatalysts for oxygen reduction.

The replacement of scarce and expensive platinum species poses a challenge in fuel-cell development. The design and synthesis of a novel type of Co(II) -N4 macrocyclic complex, [CoN4 ], based on the phenanthroline-indole macrocyclic ligand (PIM) is reported. This unique ligand allows the formation of mono- and dinuclear complexes with defined active sites that facilitate the direct four-electron reduction of oxygen. Electrochemical measurements revealed that the [CoN4 ]/C (20 wt %) catalysts have a high activity and long-term stability for the oxygen-reduction reaction (ORR) under alkaline conditions, similar to the Pt/C catalyst. These structurally well-defined complexes represent a nonprecious alternative to platinum species for future fuel-cell applications.

Concise synthesis of 3D π-extended polyphenylene cylinders.

The synthesis of structurally well-defined, monodisperse carbon nanotube (CNT) sidewall segments poses a challenge in materials science. The synthesis of polyphenylene cylinders that comprise typical benzene connectivity to resemble precursors of [9,9] and [15,15] CNTs is now reported, and the products were characterized by X-ray crystallography. To investigate the oxidative cyclodehydrogenation of ring-strained molecules as a final step towards a bottom-up synthesis of CNT sidewall segments, phenylene-extended cyclic p-hexaphenylbenzene trimers ([3]CHPB) were prepared, and NMR studies revealed a strain-induced 1,2-phenyl shift. It was further shown that an increase in ring size leads to selectively dehydrogenated macrocycles. Larger homologues are envisioned to give smooth condensation reactions toward graphenic sidewalls and should be used in the future as seeds for CNT formation.