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The formation and detailed spectroscopic characterization of the first biuret-containing monoanionic superoxido-NiII intermediate [LNiO2 ]- as the Li salt [2; L=MeN[C(=O)NAr)2 ; Ar=2,6-iPr2 C6 H3 )] is reported. It results from oxidation of the corresponding [Li(thf)3 ]2 [LNiII Br2 ] complex M with excess H2 O2 in the presence of Et3 N. The [LNiO2 ]- core of 2 shows an unprecedented nucleophilic reactivity in the oxidative deformylation of aldehydes, in stark contrast to the electrophilic character of the previously reported neutral Nacnac-containing superoxido-NiII complex 1, [L'NiO2 ] (L'=CH(CMeNAr)2 ). According to density-functional theory (DFT) calculations, the remarkably different behaviour of 1 versus 2 can be attributed to their different charges and a two-state reactivity, in which a doublet ground state and a nearby spin-polarized doublet excited-state both contribute in 1 but not in 2. The unexpected nucleophilicity of the superoxido-NiII core of 2 suggests that such a reactivity may also play a role in catalytic cycles of Ni-containing oxygenases and oxidases.

The rapid and sensitive classification of bacteria is the first step of bacterial community research and the treatment of infection. Herein, a fluorescent probe BacGO is presented, which shows the best universal selectivity for Gram-positive bacteria among known probes with a minimum staining procedure for sample detection and enrichment of the live bacteria. BacGO could also be used to assess of the Gram status in the bacterial community from wastewater sludge. Furthermore, BacGO could sensitively and selectively detect a Gram-positive bacterial infection, not only in vitro but also using an in vivo keratitis mouse model. BacGO provides an unprecedented research tool for the study of dynamic bacterial communities and for clinical application.

Pharmaceutical and agrochemical discovery programs are under considerable pressure to meet increasing global demand and thus require constant innovation. Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market place, but an obvious omission is that of the Platonic solid cubane. Eaton, however, suggested that this molecule has the potential to act as a benzene bioisostere. Herein, we report the validation of Eaton's hypothesis with cubane derivatives of five molecules that are used clinically or as agrochemicals. Two cubane analogues showed increased bioactivity compared to their benzene counterparts whereas two further analogues displayed equal bioactivity, and the fifth one demonstrated only partial efficacy. Ramifications from this study are best realized by reflecting on the number of bioactive molecules that contain a benzene ring. Substitution with the cubane scaffold where possible could revitalize these systems, and thus expedite much needed lead candidate identification.

Diazirines are an attractive class of potential molecular tags for magnetic resonance imaging owing to their biocompatibility and ease of incorporation into a large variety of molecules. As recently reported, (15)N(2)-diazirine can be hyperpolarized by the SABRE-SHEATH method, sustaining both singlet and magnetization states, thus offering a path to long-lived polarization storage. Herein, we show the generality of this approach by illustrating that the diazirine tag alone is sufficient for achieving excellent signal enhancements with long-lasting polarization. Our investigations reveal the critical role of Lewis basic additives, including water, on achieving SABRE-promoted hyperpolarization. The application of this strategy to a (15)N(2)-diazirine-containing choline derivative demonstrates the potential of (15)N(2)-diazirines as molecular imaging tags for biomedical applications.

Gephyrin is the central scaffolding protein for inhibitory neurotransmitter receptors in the brain. Here we describe the development of dimeric peptides that inhibit the interaction between gephyrin and these receptors, a process which is fundamental to numerous synaptic functions and diseases of the brain. We first identified receptor-derived minimal gephyrin-binding peptides that displayed exclusive binding towards native gephyrin from brain lysates. We then designed and synthesized a series of dimeric ligands, which led to a remarkable 1220-fold enhancement of the gephyrin affinity (KD=6.8 nM). In X-ray crystal structures we visualized the simultaneous dimer-to-dimer binding in atomic detail, revealing compound-specific binding modes. Thus, we defined the molecular basis of the affinity-enhancing effect of multivalent gephyrin inhibitors and provide conceptually novel compounds with therapeutic potential, which will allow further elucidation of the gephyrin-receptor interplay.

Okadaic acid (OA, 1) and its analogues—dinophysistoxin-1 (DTX-1, 2) and -2 (DTX-2, 3)—accumulated in mussels feeding on certain marine algae species, are causative agents of “diarrhetic shellfish poisoning” throughout the world. Okadaic acid and naturally occurring biosynthetic variants have demonstrated both potent protein serine-threonine phosphatase (PPase) inhibitory activities and apoptosisinducing activities among numerous cancerous cell lines. Circumstantially, these activities appear to be causally related. Thus, elucidating the structural basis of selective and potent OA-type PPase inhibition may underlie the discovery of novel anticancer leads. Herein, we disclose the first total synthesis of 3 and its nonnatural analogue 2-epi-3, and their PPase inhibitory activities.

Besser als das Original: Neuartige Analoga von Apicidin, einem cyclischen Tetrapeptidinhibitor der Histon-Desacetylase (HDAC), enthalten ein 1,4- oder 1,5-disubstituiertes 1,2,3-Triazol anstelle einer Gerust-Amidbindung, um die entsprechende Bindung in trans- oder cis-Konfiguration zu fixieren. So lies sich die Bindungsaffinitat unterschiedlicher Peptidkonformationen (siehe Bild) untersuchen. Ein Analogon erwies sich in einigen Fallen als ein dem Apicidin uberlegener HDAC-Inhibitor.

National Natural Science Foundation of China [20433040, 20573085, 20673091]; "973" Program [2009CB220102]

Among sheet/sheet polynuclear aromatic hydrocarbon (PAH) hybrids, a buckybowl-graphene hybrid has been used as a model to explore the effects of physical properties of PAHs with distinct planar and bowl regions. Activation of a C(Ar)-F bond was used to synthesize this corannulene/graphenic hybrid. Photophysical and voltammetric studies together with high-level computations revealed curvature and extended π-effects on the properties of these materials.

Bei einer Reihe von Antibiotika konnte eine Modifikation von Wirtsfunktionen neben ihrer antimikrobiellen Potenz gezeigt werden. Direkte Wirkungen betreffen phagozytare Funktionen, Chemotaxis und Lymphozytenaktivitaten. Effekte auf die Produktion und Freisetzung verschiedener Zytokine, die in den Entzundungsprozess einbezogen sind, wurden sowohl in vivo als auch in vitro untersucht. Die molekularen Mechanismen sind jedoch nicht im Detail entschlusselt. Vermutlich konnen Antibiotika immunpharmakologische Effekte auf der Grundlage von Struktur-Aktivitats-Beziehungen unabhangig von ihrer antibakteriellen Aktivitat entfalten. Wir prasentieren eine Zusammenstellung klinischer Studien und Fallberichte, die einen Erfolg systemisch applizierter Antibiotika im Krankheitsverlauf ausgewahlter Dermatosen beschreiben, die primar als nicht infektios klassifiziert sind. Therapiestandards, wie beispielsweise Dapson bei Dermatitis herpetiformis und leukozytoklastischer Vaskulitis oder Chloroquin in der Behandlung des Lupus erythematodes, wurden nicht berucksichtigt. Auf der Basis bisheriger klinischer Studien hoherer Fallzahl ergeben sich begrundete Hinweise fur eine Wirksamkeit folgender Antibiotika: Erythromycin beim bullosen Pemphigoid und bei der Pityriasis rosea sowie Tetracycline beim Pemphigus vulgaris, bullosen Pemphigoid und bei der Pustulosis palmaris et plantaris. Die meisten Berichte sind jedoch aufgrund des unkontrollierten Studiendesigns insbesondere bei Dermatosen mit einer Tendenz zur Spontanremission kritisch anzusehen. Trotz dieses Mangels an Evidenzdaten ist fur den Kliniker das Wissen um den potenziellen Einsatz von Antibiotika fur verschiedene Hauterkrankungen als primare Behandlungsoption oder steroideinsparende Therapieerweiterung wichtig. In der klinischen Praxis hangt die Antibiotikagabe von mehreren Faktoren ab, insbesondere von der Schwere der Erkrankung, dem Alter des Patienten, Kontraindikationen gegenuber Immunsuppressiva und nicht zuletzt von Kostenaspekten.

By building key structural features into hydrophilic drugs, they can be recognized by the PepT1 transporter system of the small intestine and rendered orally active. The model shown provides, for the first time, a 3D template for all known substrates of PepT1.

Mostofthedrugsavailabletodayforthetreatmentofcancerarebasedontheinhibitionofcellproliferationandinductionofcelldeathbyapoptosis.Atthemolecularlevel,themajorityofcytotoxicagentsinterferewithDNAfunction.However,aprominent subclass of compounds, including paclitaxel(taxol), exert their cytotoxic activity by perturbing micro-tubuledynamics.In1993,Hfle,Reichenbach,andcoworkersreportedtheisolationandcharacterizationofanovelclassofcytotoxic polyketide macrolides from the myxobacteriumSorangiumcellulosum,whichwerenamedepothilones(1).