Photoredox catalysis under shear using thin film vortex microfluidics.

A microfluidic vortex fluidic device (VFD) operating in either confined or continuous mode is effective in high yielding photoredox reactions involving Rose Bengal, with short reaction times. This processing can be translated to multi-components reactions, also with significantly reduced processing times relative to batch processing and channel microfluidic processing, with comparable or improved yields.

An interactive database to explore herbicide physicochemical properties.

Herbicides are an essential tool not only in weed management, but also in conservation tillage approaches to cropping. The first commercial herbicides were released in the 1940s and hundreds more since then, although genetic resistance to them is an issue. Here, we review the experimental and estimated physicochemical properties of 334 successful herbicidal compounds and make available a dynamic electronic database containing detailed analyses of the main chemical properties for herbicides and which adopts the Simplified Molecular-Input Line-Entry System (SMILES) for describing the structure of chemical molecules. This fully available resource allows for the rapid comparison of potential new herbicidal compounds to the chemical properties of known herbicides.

A simple and robust preparation of N-acetylindoxyls: precursors for indigogenic substrates.

A generalised, simple and efficient synthesis of N-acetyl-5-bromo-4-chloroindoxyl and related analogues required for the synthesis of indigogenic substrates to probe for biological activities is reported. The method is both synthetically and operationally simple and represents a significant improvement on existing methods.

Towards aryl C-N bond formation in dynamic thin films.

C-N bond forming reactions are important in organic chemistry. A thin film microfluidic vortex fluidic device (VFD) operating under confined mode affords N-aryl compounds from 2-chloropyrazine and the corresponding amine, without the need for a transition metal catalyst.

The monoamine re-uptake inhibitor UWA-101 improves motor fluctuations in the MPTP-lesioned common marmoset.

BACKGROUND: The wearing-OFF phenomenon is a common motor complication of chronic L-3,4-dihydroxyphenylalanine (L-DOPA) therapy for Parkinson's disease. We recently described the discovery of UWA-101, a dual serotonin (SERT) and dopamine (DAT) transporter inhibitor, which increases the duration of "good quality" ON-time provided by L-DOPA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Here, we further characterise the effects of UWA-101 on this extension of ON-time in terms of L-DOPA-induced side-effects in the MPTP-lesioned common marmoset. METHODS: Marmosets were rendered parkinsonian by MPTP injection and "primed" by repeated L-DOPA administration, to exhibit dyskinesia and psychosis-like behaviours. Animals were then administered acute challenges of L-DOPA in combination with UWA-101 (1, 3, 6 and 10 mg/kg) or vehicle. RESULTS: In combination with L-DOPA, UWA-101 (3, 6 and 10 mg/kg) significantly increased duration of ON-time (by 28%, 28%, and 33%, respectively; all P<0.05). UWA-101 (10 mg/kg) significantly extended duration of ON-time without disabling dyskinesia (by 62%, P<0.01). UWA-101 did not exacerbate the severity of dyskinesia (P>0.05). However, at the highest doses (6 and 10 mg/kg), UWA-101 increased the severity of psychosis-like behaviours (P<0.05). CONCLUSIONS: Our results demonstrate that dual SERT/ DAT inhibitors can effectively enhance L-DOPA anti-parkinsonian action, without exacerbating dyskinesia and, as such, represent a promising new therapeutic class for wearing-OFF. However, at higher doses, dual SERT/ DAT inhibitors may exacerbate dopaminergic psychosis.

A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates.

Treatment of Parkinson's disease with dopaminergic agents, such as l-DOPA, is frequently compromised by disabling side effects, particularly dyskinesia and a shortening in duration of antiparkinsonian action. Studies in animal models and anecdotal evidence from a patient with Parkinson's disease show that the illicit drug ecstasy (MDMA) can alleviate these side effects, though with many drawbacks (e.g., psychoactivity). MDMA itself thus has little therapeutic potential. On the basis of known structure-psychoactivity relationships, we designed a series of α-substituted MDMA analogues, one of which, bearing an α-cyclopropyl substituent (UWA-101), enhanced the quality of l-DOPA actions in animal models. Indeed, UWA-101 was more effective than MDMA. Unlike MDMA, UWA-101 did not reduce viability of serotonergic cells, exhibit psychoactive properties, or reduce food intake, and did not substitute for MDMA in drug discrimination assays. UWA-101 displayed a unique receptor/transporter binding profile relative to MDMA, with a >5-fold decrease in affinity for NET and 5-HT(2A) receptors and a 10-fold increase in affinity for DAT. Furthermore, in a functional reuptake assay, UWA-101 inhibited both 5-HT and dopamine reuptake, while having no effect on the reuptake of noradrenaline. UWA-101 is the first selective DAT/SERT inhibitor described with comparable affinities for these two sites. These data identify a new class of therapeutic in Parkinson's disease and highlight the potential benefits of studying illicit drugs that in themselves would never be considered safe for long-term therapy.

Enhancing the anti-lymphoma potential of 3,4-methylenedioxymethamphetamine ('ecstasy') through iterative chemical redesign: mechanisms and pathways to cell death.

While 3,4-methylenedioxymethamphetamine (MDMA/'ecstasy') is cytostatic towards lymphoma cells in vitro, the concentrations required militate against its translation directly to a therapeutic in vivo. The possibility of 'redesigning the designer drug', separating desired anti-lymphoma activity from unwanted psychoactivity and neurotoxicity, was therefore mooted. From an initial analysis of MDMA analogues synthesized with a modified α-substituent, it was found that incorporating a phenyl group increased potency against sensitive, Bcl-2-deplete, Burkitt's lymphoma (BL) cells 10-fold relative to MDMA. From this lead, related analogs were synthesized with the 'best' compounds (containing 1- and 2-naphthyl and para-biphenyl substituents) some 100-fold more potent than MDMA versus the BL target. When assessed against derived lines from a diversity of B-cell tumors MDMA analogues were seen to impact the broad spectrum of malignancy. Expressing a BCL2 transgene in BL cells afforded only scant protection against the analogues and across the malignancies no significant correlation between constitutive Bcl-2 levels and sensitivity to compounds was observed. Bcl-2-deplete cells displayed hallmarks of apoptotic death in response to the analogues while BCL2 overexpressing equivalents died in a caspase-3-independent manner. Despite lymphoma cells expressing monoamine transporters, their pharmacological blockade failed to reverse the anti-lymphoma actions of the analogues studied. Neither did reactive oxygen species account for ensuing cell death. Enhanced cytotoxic performance did however track with predicted lipophilicity amongst the designed compounds. In conclusion, MDMA analogues have been discovered with enhanced cytotoxic efficacy against lymphoma subtypes amongst which high-level Bcl-2--often a barrier to drug performance for this indication--fails to protect.

A general method for affinity-based proteomic profiling of exo-α-glycosidases.

Synthesis of iminosugar-based affinity-based proteomics probes for use in probing exo-α-glycosidase activity.

Physical and crystallographic characterisation of the mGlu5 antagonist MTEP and its monohydrochloride.

An improved medium scale synthesis of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), a selective and potent metabotropic glutamate subtype 5 (mGlu5) antagonist, has allowed thorough characterisation of the crystal structures of the free base and the previously unreported hydrochloride (MTEP.HCl). Hirshfeld surface analysis has revealed that molecules in crystalline MTEP are weakly polar, and aggregate through nonclassical C--H...N hydrogen bonds. A strong ionic N--H(+)...Cl(-) hydrogen bond dominates the crystal packing in MTEP.HCl. Despite significant differences in the crystal packing, the molecular structures of MTEP and MTEP.HCl are very similar. The acid dissociation constants for MTEP were investigated using (1)H NMR spectroscopy. The second acid dissociation constant (pK(a2)), associated with the pyridine nitrogen, was determined to be 3.40 +/- 0.01, whilst pK(a1), associated with the thiazole nitrogen, was estimated to be 0.2. The low pK(a) values make it unlikely that MTEP is protonated in its biologically active form.

Synthesis of kalasinamide, a putative plant defense phototoxin.

The first total synthesis of the azaanthracene kalasinamide (1) is described, and the discrepancy in the reported (13)C NMR data and melting points for the natural product from two different sources is resolved. Kalasinamide is prone to autosensitized photooxidation, in solution and in the solid state, to give the corresponding quinone, marcanine A (8). This transformation may be representative of a novel and more general step in the biosynthesis of (aza)anthraquinones. Through its ability to generate toxic singlet oxygen, kalasinamide may serve a protective role, defending the plant against predation and the invasion of microbial pathogens, following mechanical insult.

Enzymatic metabolism of ergosterol by cytochrome p450scc to biologically active 17alpha,24-dihydroxyergosterol.

We demonstrate the metabolism of ergosterol by cytochrome P450scc in either a reconstituted system or isolated adrenal mitochondria. The major reaction product was identified as 17alpha,24-dihydroxyergosterol. Purified P450scc also generated hydroxyergosterol as a minor product, which is probably an intermediate in the synthesis of 17alpha,24-dihydroxyergosterol. In contrast to cholesterol and 7-dehydrocholesterol, cleavage of the ergosterol side chain was not observed. NMR analysis clearly located one hydroxyl group to C24, with evidence that the second hydroxyl group is at C17. 17alpha,24-Dihydroxyergosterol inhibited cell proliferation of HaCaT keratinocytes and melanoma cells. Thus, in comparison with cholesterol and 7-dehydrocholesterol, the 24-methyl group and the C22-C23 double bond of ergosterol prevent side chain cleavage by P450scc and change the enzyme's hydroxylase activity from C22 and C20, to C24 and C17, generating bioactive product.