Cyanation of aryl bromides with K4[Fe(CN)6] catalyzed by Dichloro[bis{1-(dicyclohexylphosphanyl)piperidine}]palladium, a molecular source of nanoparticles, and the reactions involved in the catalyst-deactivation processes

Dichloro[bis{1-(dicyclohexylphosphanyl)piperidine}]palladium [(P{(NC(5)H(10))(C(6)H(11))(2)})(2)PdCl(2)] (1) is a highly active and generally applicable C-C cross-coupling catalyst. Apart from its high catalytic activity in Suzuki, Heck, and Negishi reactions, compound 1 also efficiently converted various electronically activated, nonactivated, and deactivated aryl bromides, which may contain fluoride atoms, trifluoromethane groups, nitriles, acetals, ketones, aldehydes, ethers, esters, amides, as well as heterocyclic aryl bromides, such as pyridines and their derivatives, or thiophenes into their respective aromatic nitriles with K(4)[Fe(CN)(6)] as a cyanating agent within 24 h in NMP at 140°C in the presence of only 0.05 mol % catalyst. Catalyst-deactivation processes showed that excess cyanide efficiently affected the molecular mechanisms as well as inhibited the catalysis when nanoparticles were involved, owing to the formation of inactive cyanide complexes, such as [Pd(CN)(4)](2-), [(CN)(3)Pd(H)](2-), and [(CN)(3)Pd(Ar)](2-). Thus, the choice of cyanating agent is crucial for the success of the reaction because there is a sharp balance between the rate of cyanide production, efficient product formation, and catalyst poisoning. For example, whereas no product formation was obtained when cyanation reactions were examined with Zn(CN)(2) as the cyanating agent, aromatic nitriles were smoothly formed when hexacyanoferrate(II) was used instead. The reason for this striking difference in reactivity was due to the higher stability of hexacyanoferrate(II), which led to a lower rate of cyanide production, and hence, prevented catalyst-deactivation processes. This pathway was confirmed by the colorimetric detection of cyanides: whereas the conversion of β-solvato-α-cyanocobyrinic acid heptamethyl ester into dicyanocobyrinic acid heptamethyl ester indicated that the cyanide production of Zn(CN)(2) proceeded at 25°C in NMP, reaction temperatures of >100°C were required for cyanide production with K(4)[Fe(CN)(6)]. Mechanistic investigations demonstrate that palladium nanoparticles were the catalytically active form of compound 1

Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing

Efficient genome editing with Cas9-sgRNA in vivo has required the use of viral delivery systems, which have limitations for clinical applications. Translational efforts to develop other RNA therapeutics have shown that judicious chemical modification of RNAs can improve therapeutic efficacy by reducing susceptibility to nuclease degradation. Guided by the structure of the Cas9-sgRNA complex, we identify regions of sgRNA that can be modified while maintaining or enhancing genome-editing activity, and we develop an optimal set of chemical modifications for in vivo applications. Using lipid nanoparticle formulations of these enhanced sgRNAs (e-sgRNA) and mRNA encoding Cas9, we show that a single intravenous injection into mice induces >80% editing of Pcsk9 in the liver. Serum Pcsk9 is reduced to undetectable levels, and cholesterol levels are significantly lowered about 35% to 40% in animals. This strategy may enable non-viral, Cas9-based genome editing in the liver in clinical settings

Searching for VHE gamma-ray emission associated with IceCube neutrino alerts using FACT, H.E.S.S., MAGIC, and VERITAS

The realtime follow-up of neutrino events is a promising approach to search for astrophysical neutrino sources. It has so far provided compelling evidence for a neutrino point source: the flaring gamma-ray blazar TXS 0506+056 observed in coincidence with the high-energy neutrino IceCube-170922A detected by IceCube. The detection of very-high-energy gamma rays (VHE, E>100GeV E > 100 G e V ) from this source helped establish the coincidence and constrained the modeling of the blazar emission at the time of the IceCube event. The four major imaging atmospheric Cherenkov telescope arrays (IACTs) - FACT, H.E.S.S., MAGIC, and VERITAS - operate an active follow-up program of target-of-opportunity observations of neutrino alerts sent by IceCube. This program has two main components. One are the observations of known gamma-ray sources around which a cluster of candidate neutrino events has been identified by IceCube (Gamma-ray Follow-Up, GFU). Second one is the follow-up of single high-energy neutrino candidate events of potential astrophysical origin such as IceCube-170922A. GFU has been recently upgraded by IceCube in collaboration with the IACT groups. We present here recent results from the IACT follow-up programs of IceCube neutrino alerts and a description of the upgraded IceCube GFU system