Synthesis of malhamensilipin A exploiting iterative epoxidation/chlorination: experimental and computational analysis of epoxide-derived chloronium ions

We report a 12-step catalytic enantioselective formal synthesis of malhamensilipin A (3) and diastereoisomeric analogues from (E)-2-undecenal. The convergent synthesis relied upon iterative epoxidation and phosphorus(V)-mediated deoxydichlorination reactions as well a titanium-mediated epoxide-opening to construct the C11-C16 stereohexad. The latter transformation occurred with very high levels of stereoretention regardless of the C13 configuration of the parent epoxide, implicating anchimeric assistance of either the γ- or δ-chlorine atoms, and the formation of chloretanium or chlorolanium ions, respectively. A computational analysis of the chloronium ion intermediates provided support for the involvement of chlorolanium ions, whereas the potential chloretanium ions were found to be less likely intermediates on the basis of their greater carbocationic characte

Near Infrared Light Activates Molecular Nanomachines to Drill Into and Kill Cells

Using two-photon excitation (2PE), molecular nanomachines (MNMs) are able to drill through cell membranes and kill the cells. This avoids the use of the more damaging ultraviolet (UV) light that has been used formerly to induce this nanomechanical cell-killing effect. Since 2PE is inherently confocal, enormous precision can be realized. The MNMs can be targeted to specific cell surfaces through peptide addends. Further, the efficacy was verified through controlled opening of synthetic bilayer vesicles using the 2PE excitation of MNM that had been trapped within the vesicles

Molecular machines open cell membranes

Beyond the more common chemical delivery strategies, several physical techniques are used to open the lipid bilayers of cellular membranes. These include using electric and magnetic fields, temperature, ultrasound or light to introduce compounds into cells, to release molecular species from cells or to selectively induce programmed cell death (apoptosis) or uncontrolled cell death (necrosis). More recently, molecular motors and switches that can change their conformation in a controlled manner in response to external stimuli have been used to produce mechanical actions on tissue for biomedical applications. Here we show that molecular machines can drill through cellular bilayers using their molecular-scale actuation, specifically nanomechanical action. Upon physical adsorption of the molecular motors onto lipid bilayers and subsequent activation of the motors using ultraviolet light, holes are drilled in the cell membranes. We designed molecular motors and complementary experimental protocols that use nanomechanical action to induce the diffusion of chemical species out of synthetic vesicles, to enhance the diffusion of traceable molecular machines into and within live cells, to induce necrosis and to introduce chemical species into live cells. We also show that, by using molecular machines that bear short peptide addends, nanomechanical action can selectively target specific cell-surface recognition sites. Beyond the in vitroapplications demonstrated here, we expect that molecular machines could also be used in vivo, especially as their design progresses to allow two-photon, near-infrared and radio-frequency activation

Perylene Diimide as a Precise Graphene-like Superoxide Dismutase Mimetic

Here we show that the active portion of a graphitic nanoparticle can be mimicked by a perylene diimide (PDI) to explain the otherwise elusive biological and electrocatalytic activity of the nanoparticle construct. Development of molecular analogues that mimic the antioxidant properties of oxidized graphenes, in this case the poly(ethylene glycolated) hydrophilic carbon clusters (PEG–HCCs), will afford important insights into the highly efficient activity of PEG–HCCs and their graphitic analogues. PEGylated perylene diimides (PEGn–PDI) serve as well-defined molecular analogues of PEG–HCCs and oxidized graphenes in general, and their antioxidant and superoxide dismutase-like (SOD-like) properties were studied. PEGn–PDIs have two reversible reduction peaks, which are more positive than the oxidation peak of superoxide (O2•–). This is similar to the reduction peak of the HCCs. Thus, as with PEG–HCCs, PEGn–PDIs are also strong single-electron oxidants of O2•–. Furthermore, reduced PEGn–PDI, PEGn–PDI•–, in the presence of protons, was shown to reduce O2•– to H2O2 to complete the catalytic cycle in this SOD analogue. The kinetics of the conversion of O2•– to O2 and H2O2 by PEG8–PDI was measured using freeze-trap EPR experiments to provide a turnover number of 133 s–1; the similarity in kinetics further supports that PEG8–PDI is a true SOD mimetic. Finally, PDIs can be used as catalysts in the electrochemical oxygen reduction reaction in water, which proceeds by a two-electron process with the production of H2O2, mimicking graphene oxide nanoparticles that are otherwise difficult to study spectroscopically

Mechanisms of novel thiol-disulfide oxidoreductases

Proteine der Thioredoxin-Superfamilie spielen eine bedeutende Rolle in der belebten Welt. In dieser Arbeit wurden neue Mitglieder dieser Proteinfamilie aus dem Global Ocean Sampling Metagenomprojekt (GOS) identifiziert und charakterisiert. Die Thioredoxin-Superfamilie wurde mit Hilfe von bioinformatischen Techniken definiert. Insgesamt wurden so 100 repräsentative Proteine ausgewählt. Diese Proteine waren dann Grundlage für Gensynthesen. In Komplementationsstudien wurden diese 100 Proteine mit Hilfe von $\textit {Escherichia coli}$ Mutanten auf Reduktions-, Oxidations- und Isomerisierungsaktivität getestet. 8 positive Proteinkandidaten wurden für weitere $\textit {in vitro}$ Analysen ausgewählt. Es wurden die Insulin-Reduktions-Aktivtät und das Redoxpotenzial bestimmt. Zusammenfassend liefert diese Studie einen Beitrag zum Verständnis der Evolution der Thioredoxin-Superfamilie und untermauert ihr hohes Maß an Plastizität. Des Weiteren wird hier ein methodischer Ablauf für funktionelle Metagenomik etabliert