Classical and microwave-assisted synthesis of cucurbit[n]urils, hemicucurbit[n]urils and bambus[n]urils

This chapter gives a concise overview of the synthetic and supramolecular chemistry of cucurbit[n]uril (CB[n]) family of macrocycles and expands it to hemicucurbit[n]urils (HemCB[n]) and bambus[n]urils (BU[n]). The application of microwave-assisted synthesis to access these macrocycles is reviewed. Several extensive papers describing the synthesis, physical and recognition properties and applications of CB[n]s have been published and the reader is directed to these key sources throughout this chapter

The M-CAT's out of the bag: A paper-based microfluidic immunoassay for the rapid detection of mephedrone

This paper reports a paper-based microfluidic competitive immunoassay for the detection of mephedrone, a new psychoactive substance (NPS). Using the proposed system, limits of detection of 4.078 μg mL-1 and 1.597 μg mL-1 for aqueous mephedrone and spiked urine samples, respectively, were obtained, with these values enabling the detection of clinically relevant concentrations of mephedrone. The proposed device has the opportunity to provide rapid, on-site testing, within either a forensic or clinical setting, for NPSs

Guilty by dissociation: Paper-fluidic presumptive testing of the new psychoactive substance, diphenidine

This paper reports a paper microfluidic device which can presumptively test for the new psychoactive substance (NPS), diphenidine. A simple 'dip-stick' test has been developed in which Scott's and Marquis reagents are stored on the paper-fluidic device and a colour change is observed upon sample addition if the drug is present. The limit of detection for diphenidine was determined to be 2.5 mg mL-1 and 5 mg mL-1 for the Scott's and Marquis reagents, respectively, which is within the range normally found within bulk samples encountered by law enforcement agencies. A range of street samples were tested and the results showed strong correlation with conventional laboratory methods

Regal electrochemistry: Sensing of the synthetic cathinone class of new psychoactive substances (NPSs)

© 2015 The Royal Society of Chemistry. In this paper the concept of 'Regal Electrochemistry' is expanded towards the electrochemical sensing of Novel Psychoactive Substances (NPSs) namely synthetic cathinone derivatives where British coinage is used as the electrochemical sensor. In this proof-of-concept approach, the electrochemical sensing of mephedrone (4-MMC) and 4′-methyl-N-ethylcathinone (4-MEC) is shown to be possible using a British 1 pence coin for the first time. This novel electrochemical protocol is validated towards the detection of cathinone derivatives in a seized street sample that has been independently analysed via high performance liquid chromatography demonstrating its potential use as a novel electrochemical sensor for NPSs

Forensic electrochemistry: the electroanalytical sensing of synthetic cathinone-derivatives and their accompanying adulterants in "legal high" products

The production and abuse of new psychoactive substances, known as “legal highs” which mimic traditional drugs of abuse is becoming a global epidemic. Traditional analytical methodologies exist which can provide confirmatory analysis but there is a requirement for an on-the-spot analytical screening tool that could be used to determine whether a substance, or sample matrix contains such legal, or formally “legal highs”. In this paper the electrochemical sensing of ( )-methcathinone and related compounds at a range of commercially available electrode substrates is explored. We demonstrate for the first time that this class of “legal highs” are electrochemically active providing a novel sensing protocol based upon their electrochemical oxidation. Screen-printed graphite sensing platforms are favoured due to their proven ability to be mass-produced providing large numbers of reliable and reproducible electrode sensing platforms that preclude the requirement of surface pre-treatment such as mechanical polishing as is the case in the use of solid/re-usable electrode substrates. Additionally they hold potential to be used on-site potentially being the basis of an on-site legal high screening device. Consequently the electroanalytical sensing of ( )-methcathinone (3a), ( )-40-methylmethcathinone [3b, 4-MMC, ( )-mephedrone] and ( )-40-methyl-N-ethylcathinone (3c, 4-MEC) is explored using screen-printed sensing platforms with the effect of pH explored upon the analytical response with their analytical efficiency evaluated towards the target legal highs. Interesting at pH values below 6 the voltammetric response quantitatively changes from that of an electrochemically irreversible response to that of a quasi-reversible signature which can be used analytically. It is demonstrated for the first time that the electroanalytical sensing of ( )-methcathinone (3a), ( )-mephedrone (3b) and 4-MEC (3c) are possible with accessible linear ranges found to correspond to 16–200 mg mL 1 for 3a (at pH 12) and 16–350 mg mL 1 for both 3b and 3c in pH 2, with limits of detection (3s) found to correspond to 44.5, 39.8 and 84.2 mg mL 1 respectively. Additionally adulterants that are commonly incorporated into cathinone legal highs are electrochemically explored at both pH 2 and 12

Identification of Novel Metabolic Pathways of Sitagliptin (STG) by LC/MS and LC/MS2 after Incubations with Rat Hepatocytes

Sitagliptin (STG), a drug for treating Type Ii Diabetes Mellitus (T2DM), has been associated with severe joint pain in some patients. In this paper the metabolic profile of the drug has been investigated in order to determine metabolism and formation of reactive compounds which may contribute to this adverse effect. Metabolism of STG was investigated in vitro by incubation with freshly isolated Sprague-Dawley rat hepatocytes, to characterize Phase I and II metabolites, and the reaction mixture analysed on a zwitter ionic hydrophilic interaction (ZIC®-HILIC) column using LC-MS and LC-MS2 utilising electrospray ionization (ESI) in the positive ion mode. STG was metabolised to yield eleven metabolites, but in total only 3.1% of the parent drug was metabolised over 2 hrs incubation. These metabolites were structurally characterized on the basis of accurate mass analyses and the major metabolic routes for STG determined to be via aromatic oxidation (0.86%) and desaturation of N-C and C-C of the piperazine (0.44%). Novel metabolites of STG detected using these methods included STG N-glucuronide (M6) and a di-ketone metabolite (M4), hydroxylation of both the amine group and aromatic ring followed by formation of glucuronide metabolites (M5, M5’), oxidative desaturation of NH2 and di-hydroxylation of metabolites followed by loss of HF. Also, observed was an N-sulfate metabolite (0.07%) and acetylation followed by glucuronide conjugation was also found in trace amounts (<0.01%). MS2 fragment ions provide additional structural confirmation providing a possible structure for most metabolites such as by fragment ion loss of the glucuronide group (176 Da) from metabolite M5 and loss of the phenolic sulfate (80 Da) of N-Sulfate metabolite (M7). Reduction reaction of piperazine ring probably generates highly electrophilic metabolite of STG, which may be susceptible to produce adverse effects. Furthermore, N-oxidation reaction forming reactive intermediates metabolic to give a hydroxylamine metabolite that may undergo further reactions to yield electrophilic intermediate metabolites

Structural elucidation of unknowns: a spectroscopic investigation with an emphasis on 1D and 2D nuclear magnetic resonance spectroscopy

Nuclear Magnetic Resonance (NMR) spectroscopy is a widely used technique for structural elucidation. It is often used in conjunction with other complimentary analytical techniques such as infra-red (IR) and mass spectrometry (MS) to completely assign the chemical structure of molecules. For undergraduate students, gaining familiarity with NMR is often difficult as they rarely have the opportunity to collect this data for themselves; often they are just provided with spectra to interpret. We have developed an experiment that tasks students with obtaining 1D and 2D 1H NMR data of two unknowns, and then using 13C NMR, CHN elemental microanalysis, MS and IR data, to elucidate fully their two structures. The experiment provides students with an experiential learning opportunity for 1H NMR whilst also developing and strengthening their structural elucidation skills

Chromatographic retention behaviour, modelling and optimization of a UHPLC-UV separation of the regioisomers of the Novel Psychoactive Substance (NPS) methoxphenidine (MXP)

© 2018 Elsevier B.V. A detailed investigation into the chromatographic retention behaviour and separation of the three regioisomers of the Novel Psychoactive Substance (NPS) methoxphenidine (i.e. 2-, 3- and 4-MXP isomers) has revealed the ionization state of the analyte and stationary phase, to be the controlling factor in dictating which retention mechanism is in operation. At low pH, poor separation and retention was observed. In contrast, at intermediate pH, enhanced retention and separation of the three MXP isomers was obtained; it appeared that there was a synergistic effect between the electrostatic and hydrophobic mechanisms. At high pH, the MXP isomers were retained by hydrophobic retention. Accurate retention time predictions ( 5 within 4 min) was predicted and verified. The developed methodology should be highly suitable for the rapid, specific and sensitive detection and control of MXP regioisomers

Engineering molecularly imprinted polymers (MIPs) for the selective extraction and quantification of the novel psychoactive substance (NPS) methoxphenidine and its regioisomers.

In this communication, we present the first developed Molecularly Imprinted Polymers (MIPs) for the specific detection of a New Psychoactive Substance (NPS); namely, methoxphenidine (MXP) and its regioisomers. Selectivity of the MIP towards MXP is studied by analysing mixtures and an acquired street sample with High Performance Liquid Chromatography coupled to UV detection. The study demonstrates that the engineered polymers selectively extract MXP from heterogeneous samples, which makes for a very powerful diagnostic tool that can detect traces of MXP in complicated NPS samples

Log D_7.4 and plasma protein binding of synthetic cannabinoid receptor agonists and a comparison of experimental and predicted lipophilicity

The emergence of new synthetic cannabinoid receptor agonists (SCRAs) onto the illicit drugs market continues to cause harm, and the overall availability of physicochemical and pharmacokinetic data for new psychoactive substances is lacking. The lipophilicity of 23 SCRAs and the plasma protein binding (PPB) of 11 SCRAs was determined. Lipophilicity was determined using a validated chromatographic hydrophobicity index (CHI) log D method; tested SCRAs showed moderate to high lipophilicity, with experimental log D7.4 ranging from 2.48 (AB-FUBINACA) to 4.95 (4F-ABUTINACA). These results were also compared to in silico predictions generated using seven commercially available software packages and online tools (Canvas; ChemDraw; Gastroplus; MoKa; PreADMET; SwissADME; and XlogP). Licenced, dedicated software packages provided more accurate lipophilicity predictions than those which were free or had prediction as a secondary function; however, the latter still provided competitive estimates in most cases. PPB of tested SCRAs, as determined by equilibrium dialysis, was in the upper range of the lipophilicity scale, ranging from 90.8% (ADB-BUTINACA) to 99.9% (BZO-HEXOXIZID). The high PPB of these drugs may contribute to reduced rate of clearance and extended durations of pharmacological effects compared to lesser-bound SCRAs. The presented data improve understanding of the behaviour of these drugs in the body. Ultimately, similar data and predictions may be used in the prediction of the structure and properties of drugs yet to emerge on the illicit market