Despite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnections, more C-H bond activation and late-stage functionalization, as well as stereoselectively substituted aliphatic heterocyclic ring synthesis, C-X or C-C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.

The jumonji (JMJ) family of histone demethylases are Fe2+- and α-ketoglutarate-dependent oxygenases that are essential components of regulatory transcriptional chromatin complexes1–4. These enzymes demethylate lysine residues in histones in a methylation-state and sequence-specific context5. Considerable effort has been devoted to gaining a mechanistic understanding of the roles of histone lysine demethylases in eukaryotic transcription, genome integrity and epigenetic inheritance2,4,6, as well as in development, physiology and disease3,7. However, because of the absence of any selective inhibitors, the relevance of the demethylase activity of JMJ enzymes in regulating cellular responses remains poorly understood. Here we present a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3-specific demethylase subfamily (KDM6 subfamily members JMJD3 and UTX)8. The liganded structures of human and mouse JMJD3 provide novel insight into the specificity determinants for cofactor, substrate and inhibitor recognition by the KDM6 subfamily of demethylases. We exploited these structural features to generate the first small-molecule catalytic site inhibitor that is selective for the H3K27me3-specific JMJ subfamily. We demonstrate that this inhibitor binds in a novel manner and reduces lipopolysaccharide-induced proinflammatory cytokine production by human primary macrophages, a process that depends on both JMJD3 and UTX. Our results resolve the ambiguity associated with the catalytic function of H3K27-specific JMJs in regulating disease-relevant inflammatory responses and provide encouragement for designing small-molecule inhibitors to allow selective pharmacological intervention across the JMJ family.

The SuperWASP Cameras are wide-field imaging systems sited at the Observatorio del Roque de los Muchachos on the island of La Palma in the Canary Islands, and the Sutherland Station of the South African Astronomical Observatory. Each instrument has a field of view of some ~482 square degrees with an angular scale of 13.7 arcsec per pixel, and is capable of delivering photometry with accuracy better than 1% for objects having V ~ 7.0 - 11.5. Lower quality data for objects brighter than V ~15.0 are stored in the project archive. The systems, while designed to monitor fields with high cadence, are capable of surveying the entire visible sky every 40 minutes. Depending on the observational strategy, the data rate can be up to 100GB per night. We have produced a robust, largely automatic reduction pipeline and advanced archive which are used to serve the data products to the consortium members. The main science aim of these systems is to search for bright transiting exo-planets systems suitable for spectroscopic followup observations. The first 6 month season of SuperWASP-North observations produced lightcurves of ~6.7 million objects with 12.9 billion data points.Comment: 42 pages, 2 plates, 5 figures PASP in pres

The study of transient chemical phenomena by conventional NMR has proved elusive, particularly for non-1H nuclei. For 13C, hyperpolarization using the dynamic nuclear polarization (DNP) technique has emerged as a powerful means to improve SNR. The recent development of rapid dissolution DNP methods has facilitated previously impossible in vitro and in vivo study of small molecules. This review presents the basics of the DNP technique, identification of appropriate DNP substrates, and approaches to increase hyperpolarized signal lifetimes. Also addressed are the biochemical events to which DNP-NMR has been applied, with descriptions of several probes that have met with in vivo success.

We report on the discovery of WASP-12b, a new transiting extrasolar planet with R pl = 1.79 +0.09 −0.09 R J and M pl = 1.41 +0.10 −0.10 M J . The planet and host star properties were derived from a Monte Carlo Markov chain analysis of the transit photometry and radial velocity data. Furthermore, by comparing the stellar spectrum with theoretical spectra and stellar evolution models, we determined that the host star is a supersolar metallicity ([M/H]= 0.3 +0.05 −0.15 ), late-F (T eff = 6300 +200 −100 K) star which is evolving off the zero-age main sequence. The planet has an equilibrium temperature of T eq = 2516 K caused by its very short period orbit (P = 1.09 days) around the hot, twelfth magnitude host star. WASP-12b has the largest radius of any transiting planet yet detected. It is also the most heavily irradiated and the shortest period planet in the literature.