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A parthenolide-derivative with favourable pharmacokinetic properties and good activity against drug-resistant chronic lymphocytic leukaemia is reported., Parthenolide is a natural product that exhibits anti-leukaemic activity, however, its clinical use is limited by its poor bioavailability. It may be extracted from feverfew and protocols for growing, extracting and derivatising it are reported. A novel parthenolide derivative with good bioavailability and pharmacological properties was identified through a screening cascade based on in vitro anti-leukaemic activity and calculated “drug-likeness” properties, in vitro and in vivo pharmacokinetics studies and hERG liability testing. In vitro studies showed the most promising derivative to have comparable anti-leukaemic activity to DMAPT, a previously described parthenolide derivative. The newly identified compound was shown to have pro-oxidant activity and in silico molecular docking studies indicate a prodrug mode of action. A synthesis scheme is presented for the production of amine 7 used in the generation of 5f.

Twelve 1,5-disubtituted and fourteen 5-substituted 1,2,3-triazole derivatives bearing diaryl or dialkyl phosphines at the 5-position were synthesized and used as ligands for palladium-catalyzed Suzuki–Miyaura cross-coupling reactions. Bulky substrates were tested, and lead-like product formation was demonstrated. The online tool SambVca2.0 was used to assess steric parameters of ligands and preliminary buried volume determination using XRD-obtained data in a small number of cases proved to be informative. Two modeling approaches were compared for the determination of the buried volume of ligands where XRD data was not available. An approach with imposed steric restrictions was found to be superior in leading to buried volume determinations that closely correlate with observed reaction conversions. The online tool LLAMA was used to determine lead-likeness of potential Suzuki–Miyaura cross-coupling products, from which 10 of the most lead-like were successfully synthesized. Thus, confirming these readily accessible triazole-containing phosphines as highly suitable ligands for reaction screening and optimization in drug discovery campaigns.

A series of single enantiomer, 2,4-cis-disubstituted amino azetidines were synthesised and used as ligands for copper-catalysed Henry reactions of aldehydes with nitromethane. Optimisation of ligand substituents and the reaction conditions was conducted. The enantiomeric excess of the formed products was highest when alkyl aldehydes were employed in the reaction (>99% e.e.). The absolute stereochemistry of one representative azetidine derivative salt was determined by analysis of the Flack parameter of an XRD single crystal structure. The origin of selectivity in catalysis was investigated computationally, revealing the importance of the amino-substituent in determining the stereochemical outcome. A racemic platinum complex of a cis-disubstituted azetidine is examined by XRD single crystal structure analysis with reference to its steric parameters, and analogies to the computationally determined copper complex catalyst are drawn. A preliminary example of the use of a cis-disubstituted azetidine scaffold in thiourea H-bonding catalyst is noted in the supporting information.

Alkaloid catalysed additions to triketopiperazines gives products in high yield and er (88 : 12 to 99 : 1), including bridged hydroxy-DKPs via Michael-addition–ring closure., Michael addition reactions of triketopiperazine (TKP) derivatives to enones, mediated by a cinchona alkaloid-derived catalyst, deliver products in high yield and enantiomeric ratio (er). Use of unsaturated ester, nitrile or sulfone partners gives bridged hydroxy-diketopiperazine (DKP) products resulting from a novel Michael addition–ring closure.

Blue- and green-emitting cyclometalated liquid-crystalline iridium complexes are realized by using a modular strategy based on strongly mesogenic groups attached to an acetylacetonate ancillary ligand. The cyclometalated ligand dictates the photophysical properties of the materials, which are identical to those of the parent complexes. High hole mobilities, up to 0.004 cm2 V-1 s-1, were achieved after thermal annealing, while amorphous materials show hole mobilities of only approximately 10-7-10-6 cm2 V-1 s-1, similar to simple iridium complexes. The design strategy allows the facile preparation of phosphorescent liquid-crystalline complexes with fine-tuned photophysical properties.

In an approach to the biologically important 6-azabicyclo[3.2.1]octane ring system, the scope of the tandem 4-exo-trig carbamoyl radical cyclization—dithiocarbamate group transfer reaction to ring-fused β-lactams is evaluated. β-Lactams fused to five-, six-, and seven-membered rings are prepared in good to excellent yield, and with moderate to complete control at the newly formed dithiocarbamate stereocentre. No cyclization is observed with an additional methyl substituent on the terminus of the double bond. Elimination of the dithiocarbamate group gives α,β- or β,γ-unsaturated lactams depending on both the methodology employed (base-mediated or thermal) and the nature of the carbocycle fused to the β-lactam. Fused β-lactam diols, obtained from catalytic OsO4-mediated dihydroxylation of α,β-unsaturated β-lactams, undergo semipinacol rearrangement via the corresponding cyclic sulfite or phosphorane to give keto-bridged bicyclic amides by exclusive N-acyl group migration. A monocyclic β-lactam diol undergoes Appel reaction at a primary alcohol in preference to semipinacol rearrangement. Preliminary investigations into the chemo- and stereoselective manipulation of the two carbonyl groups present in a representative 7,8-dioxo-6-azabicyclo[3.2.1]octane rearrangement product are also reported.

The UK National Crystallography Service (NCS) is an amalgamation of resources at two centres; Southampton Chemical Crystallography Group and Daresbury SRS (Newcastle component). This service provides state of the art facilities and expertise in the technique of small molecule crystal structure determination and is available to all UK academics eligible to apply to the EPSRC Chemistry programme. Throughout its 25 year existence the Service has pioneered development of the technique and provided innovations that have helped enable structural science in the UK to flourish. The Southampton rotating anode is equipped with the world's first focusing optics for molybdenum radiation provides the brightest available laboratory source dedicated to small molecule crystallography. Coupled with the latest APEX2 CCD technology and data processing software, this enables us to examine exceptionally small crystals (down to ca 10?m minimum dimensions) and deconvolute twinned or incommensurate datasets. This technology also enables us to derive structures originating from the most demanding areas of chemistry, such as supramolecular, nanomaterials and biological chemistry. In addition, high-throughput techniques have been adopted to aid the development of crystal structure prediction. Continuation funding until late 2009 has ensured that we will continue to provide these facilities for some time to come. The Service offers 'data collection only' or 'full structure determination' opportunities and specialises in handling extremely demanding samples and datasets. It also offers specialist experiments, such as charge density determinations, high- and variable-temperature data collections (80 - 500K) and multiple collections to elucidate phase transitions and structure-property relationships. For those samples that are too small or weakly diffracting for the Southampton equipment, a follow-on service is provided at the Daresbury SRS. Periodic allocations on stations 9.8 (or occasionally 16.2) permit regular investigations of these Southampton-screened samples. This arrangement ensures that only the most challenging and appropriate samples are taken to the SRS and provides rapid access to these oversubscribed world-leading facilities. Transfer to Diamond is planned for 2008. The experience and expertise of the NCS staff is passed on to UK postgraduate and postdoctoral workers at our biennial Advanced Skills Workshop (held in alternate years to the Durham BCA School). This provides insights into the handling of difficult samples and datasets, both in the home laboratory and at the synchrotron. With a throughput in excess of 1200 samples per annum the NCS has developed e-Science techniques for management of the Service and its data. This approach includes the provision of web-based application, submission, sample tracking and data download facilities for users. To cope with the increased output of structural data an innovative data-dissemination mechanism has been developed as an alternative to the conventional data publication process, creating a higher profile for data collected by the Service.