• Synthesis and Characterization of Novel Nopyl-Derived Phosphonium Ionic Liquids

      Yu, Jiangou; Wheelhouse, Richard T.; Honey, M.A.; Karodia, N. (2020-10-10)
      A series of novel nopyl-derived chiral phosphonium ionic liquids have been successfully synthesised and characterised. Analysis of each novel ionic liquid was conducted in order to confirm structure, purity and thermal stability.
    • Synthesis and controlled growth of osmium nanoparticles by electron irradiation

      Pitto-Barry, Anaïs; Perdigao, L.M.A.; Walker, M.; Lawrence, J.; Constantini, G.; Sadler, P.J.; Barry, Nicolas P.E. (2015)
      We have synthesised osmium nanoparticles of defined size (1.5–50 nm) on a B- and S-doped turbostratic graphitic structure by electron-beam irradiation of an organometallic osmium complex encapsulated in self-spreading polymer micelles, and characterised them by transmission electron microscopy (TEM), high-resolution TEM (HRTEM), and atomic force microscopy (AFM) on the same grid. Oxidation of the osmium nanoparticles after exposure to air was detected by X-ray photoelectron spectroscopy (XPS).
    • Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents.

      Wright, Colin W.; Addae-Kyereme, Jonathan A.; Breen, Anthony G.; Brown, John E.; Cox, Marlene F.; Croft, S.L.; Gokcek, Yaman; Kendrick, H.; Phillips, Roger M.; Pollet, Pamela L. (2001)
      The indoloquinoline alkaloid cryptolepine 1 has potent in vitro antiplasmodial activity, but it is also a DNA intercalator with cytotoxic properties. We have shown that the antiplasmodial mechanism of 1 is likely to be due, at least in part, to a chloroquine-like action that does not depend on intercalation into DNA. A number of substituted analogues of 1 have been prepared that have potent activities against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and also have in common with chloroquine the inhibition of ß-hematin formation in a cell-free system. Several compounds also displayed activity against Plasmodium berghei in mice, the most potent being 2,7-dibromocryptolepine 8, which suppressed parasitemia by 89% as compared to untreated infected controls at a dose of 12.5 mg kg-1 day-1 ip. No correlation was observed between in vitro cytotoxicity and the effect of compounds on the melting point of DNA (¿Tm value) or toxicity in the mouse¿malaria model.
    • Synthesis and Evaluation of Selected Benzimidazole Derivatives as Potential Antimicrobial Agents

      Alasmary, Fatmah A.S.; Snelling, Anna M.; Zain, M.E.; Alafeefy, A.M.; Awaad, A.S.; Karodia, Nazira (2015)
      A library of 53 benzimidazole derivatives, with substituents at positions 1, 2 and 5, were synthesized and screened against a series of reference strains of bacteria and fungi of medical relevance. The SAR analyses of the most promising results showed that the antimicrobial activity of the compounds depended on the substituents attached to the bicyclic heterocycle. In particular, some compounds displayed antibacterial activity against two methicillin-resistant Staphylococcus aureus (MRSA) strains with minimum inhibitory concentrations (MICs) comparable to the widely-used drug ciprofloxacin. The compounds have some common features; three possess 5-halo substituents; two are derivatives of (S)-2-ethanaminebenzimidazole; and the others are derivatives of one 2-(chloromethyl)-1H-benzo[d]imidazole and (1H-benzo[d]imidazol-2-yl)methanethiol. The results from the antifungal screening were also very interesting: 23 compounds exhibited potent fungicidal activity against the selected fungal strains. They displayed equivalent or greater potency in their MIC values than amphotericin B. The 5-halobenzimidazole derivatives could be considered promising broad-spectrum antimicrobial candidates that deserve further study for potential therapeutic applications.
    • Synthesis and growth-inhibitory activities of imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamides related to the anti-tumour drug temozolomide, with appended silicon, benzyl and heteromethyl groups at the 3-position

      Cousin, D.; Hummersone, M.G.; Bradshaw, T.D.; Zhang, J.; Moody, C.J.; Foreiter, M.B.; Summers, H.S.; Lewis, W.; Wheelhouse, Richard T.; Stevens, M.F.G. (2018)
      A series of 3-(benzyl-substituted)-imidazo[5,1-d]-1,2,3,5-tetrazines (13) and related derivatives with 3-heteromethyl groups has been synthesised and screened for growth-inhibitory activity in vitro against two pairs of glioma cell lines with temozolomide-sensitive and -resistant phenotypes dependent on the absence/presence of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In general the compounds had low inhibitory activity with GI50 values > 50 µM against both sets of cell lines. Two silicon-containing derivatives, the TMS-methylimidazotetrazine (9) and the SEM-analogue (10), showed interesting differences: compound (9) had a profile very similar to that of temozolomide with the MGMT+ cell lines being 5 to 10-fold more resistant than MGMT– isogenic partners; the SEM-substituted compound (10) showed potency across all cell lines irrespective of their MGMT status.
    • Synthesis and quantitative structure-activity relationship of imidazotetrazine prodrugs with activity independent of O6-methylguanine-DNA-methyltransferase, DNA mismatch repair, and p53

      Pletsas, Dimitrios; Garelnabi, Elrashied A.E.; Li, Li; Phillips, Roger M.; Wheelhouse, Richard T. (2013)
      The antitumor prodrug temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (E.C. 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR, and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bifunctional analogues are reported, and a quantitative structure-activity relationship (QSAR) study identified the p-tolyl-substituted bifunctional congener as optimized for potency, MGMT-independence, and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development, and their improved in vitro activity validates the principles on which they were designed.
    • Synthesis and structural studies (H-1, C-13, P-31 NMR and X-ray) of new C-bonded cyclotriphosphazenes with heterocyclic substituents from novel phosphinic acid derivatives.

      Vicente, V.; Fruchier, A.; Taillefer, M.; Coombes-Chamelet, C.; Scowen, Ian J.; Plenat, F.; Cristeau, H-J. (2004)
      Three new C-bonded cyclotriphosphazenes, [N3P3(2-thienyl)6], 2, [N3P3(3-thienyl)6], 4, and [N3P3(3,3-bithienyl-2,2-ylene)3], 6, have been prepared by two new synthetic procedures and are the first examples of non-spiro and trispirocyclotriphosphazene derivatives composed of thiophene and 3,3-dithiophene substituents, respectively. Their 1H, 13C and 31P NMR parameters are given. The solid state structures of 2, 4 and 6 have been determined by X-ray crystallography.
    • The synthesis and unexpected solution chemistry of thermochromic carborane-containing osmium half-sandwich complexes

      Pitto-Barry, Anaïs; South, A.; Rodger, A.; Barry, Nicolas P.E. (2016)
      The functionalisation of the 16-electron complex [Os(η6-p-cymene)(1,2-dicarba-closo-dodecarborane- 1,2-dithiolato)] (1) with a series of Lewis bases to give the 18-electron complexes of general formula [Os(η6-p-cymene)(1,2-dicarba-closo-dodecarborane-1,2-dithiolato)(L)] (L = pyridine (2), 4-dimethylaminopyridine (3), 4-cyanopyridine (4), 4-methoxypyridine (5), pyrazine (6), pyridazine (7), 4,4’-bipyridine (8) and triphenylphosphine (9)) is reported. All 18-electron complexes are in equilibrium in solution with the 16-electron precursor, and thermochromic properties are observed in some cases (2, 3, 5, 8, and 9). The binding constants and Gibbs free energies of the equilibria are determined using UV-visible titrations and their stabilities investigated. Synthetic routes for forcing the formation of the 18-electron species are proposed, and analytical methods to characterise the equilibria are described.
    • Synthesis by extrusion: continuous, large-scale preparation of MOFs using little or no solvent

      Crawford, Deborah E.; Casaban, J.; Haydon, R.; Giri, N.; McNally, T.; James, S.L. (2015-03)
      Grinding solid reagents under solvent-free or low-solvent conditions (mechanochemistry) is emerging as a general synthetic technique which is an alternative to conventional solvent-intensive methods. However, it is essential to find ways to scale-up this type of synthesis if its promise of cleaner manufacturing is to be realised. Here, we demonstrate the use of twin screw and single screw extruders for the continuous synthesis of various metal complexes, including Ni(salen), Ni(NCS)2(PPh3)2 as well as the commercially important metal organic frameworks (MOFs) Cu3(BTC)2 (HKUST-1), Zn(2-methylimidazolate)2 (ZIF-8, MAF-4) and Al(fumarate)(OH). Notably, Al(fumarate)(OH) has not previously been synthesised mechanochemically. Quantitative conversions occur to give products at kg h−1 rates which, after activation, exhibit surface areas and pore volumes equivalent to those of materials produced by conventional solvent-based methods. Some reactions can be performed either under completely solvent-free conditions whereas others require the addition of small amounts of solvent (typically 3–4 mol equivalents). Continuous neat melt phase synthesis is also successfully demonstrated by both twin screw and single screw extrusion for ZIF-8. The latter technique provided ZIF-8 at 4 kg h−1. The space time yields (STYs) for these methods of up to 144 × 103 kg per m3 per day are orders of magnitude greater than STYs for other methods of making MOFs. Extrusion methods clearly enable scaling of mechanochemical and melt phase synthesis under solvent-free or low-solvent conditions, and may also be applied in synthesis more generally.
    • Synthesis of caffeine/maleic acid co-crystal by ultrasound assisted slurry co-crystallization

      Apshingekar, Prafulla P.; Aher, Suyog; Kelly, Adrian L.; Brown, Elaine C.; Paradkar, Anant R. (2017-01)
      A green approach has been used for co-crystallization of non-congruent co-crystal pair of caffeine – maleic acid using water. Ultrasound is known to affect crystallization hence the effect of high power ultrasound on the ternary phase diagram has been investigated in detail using a slurry co-crystallization approach. A systematic investigation was performed to understand how the accelerated conditions during ultrasound assisted co-crystallization will affect different regions of the ternary phase diagram. Application of ultrasound showed considerable effect on the ternary phase diagram; principally on caffeine/maleic acid 2:1 (disappeared) and 1:1 co-crystal (narrowed) regions. Also, the stability regions for pure caffeine and maleic acid in water were narrowed in the presence of ultrasound, expanding the solution region. The observed effect of ultrasound on the phase diagram was correlated with solubility of caffeine and maleic acid and stability of co-crystal forms in water.
    • Synthesis of citrate-ciprofloxacin conjugates.

      Md-Saleh, S.R.; Chilvers, E.C.; Kerr, Kevin G.; Milner, S.J.; Snelling, Anna M.; Weber, J.P.; Thomas, G.H.; Duhme-Klair, A-K.; Routledge, A. (2009)
      Two regioisomeric citrate-functionalized ciprofloxacin conjugates have been synthesized and their antimicrobial activities against a panel of clinically-relevant bacteria have been determined. Cellular uptake mechanisms were investigated using wild-type and ompF deletion strains of Escherichia coli K-12.
    • Synthesis of DNA-Directed Pyrrolidinyl and Piperidinyl Confined Alkylating Chloroalkylaminoanthraquinones: Potential for Development of Tumor-Selective N-Oxides

      Patterson, Laurence H.; Pors, Klaus; Shnyder, Steven D.; Teesdale-Spittle, P.H.; Hartley, J.A.; Searcey, M.; Zloh, M. (2006)
      A novel series of 1,4-disubstituted chloroethylaminoanthraquinones, containing alkylating chloroethylamino functionalities as part of a rigid piperidinyl or pyrrolidinyl ring-system, have been prepared. The target compounds were prepared by ipso-displacement of halides of various anthraquinone chromophores by either hydroxylated or chlorinated piperidinyl- or pyrrolidinyl-alkylamino side chains. The chloroethylaminoanthraquinones were shown to alkylate guanine residues of linearized pBR322 (1¿20 ¿M), and two symmetrically 1,4-disubstituted anthraquinones (compounds 14 and 15) were shown to interstrand cross-link DNA in the low nM range. Several 1,4-disubstituted chloroethylaminoanthraquinones were potently cytotoxic (IC50 values: ¿40 nM) in human ovarian cancer A2780 cells. Two agents (compounds 18 and 19) exhibited mean GI50 values of 96 nM and 182 nM, respectively, in the NCI human tumor cell line panel. Derivatization of the potent DNA cross-linking agent 15 to an N-oxide resulted in loss of the DNA unwinding, DNA interstrand cross-linking and cytotoxic activity of the parent molecule.
    • Synthesis of iridium and ruthenium complexes with (N,N), (N,O) and (O,O) coordinating bidentate ligands as potential anti-cancer agents

      Lucas, S.J.; Lord, Rianne M.; Wilson, R.L.; Phillips, Roger M.; Sridharan, V.; McGowan, P.C. (2012-12-07)
      Several Ru-arene and Ir–Cp* complexes have been prepared incorporating (N,N), (N,O) and (O,O) coordinating bidentate ligands and have been found to be active against both HT-29 and MCF-7 cell lines. By incorporating a biologically active ligand into a metal complex the anti-cancer activity is increased.
    • Synthesis of orthogonal push-pull chromophores via click reaction of arylynamines

      Huang, S.; Ma, J.; Yi, Y.; Li, M.; Cai, P.; Wu, Na (Anna) (2022-04)
      Herein, we report a catalyst-free ‘click’ reaction: metal-free [2 + 2] cycloaddition–retro-electrocyclisation (CA–RE) of arylynamines with the sluggish acceptor tetracyanoquinodimethane (TCNQ) to provide orthogonal electron-push–pull light-harvesting small molecules: N-heterocyclic dicyanoquinodimethane-substituted methylene malononitriles. Ynamines are reactive alkynes and tend to induce over-reactions with the CA–RE adducts. The reactivity of arylynamines was balanced properly by ensuring the electrondensity of the nitrogen atom was delocalised more over the aromatic rings than the triple bond.
    • Synthesis of radioactively labelled CdSe/CdS/ZnS quantum dots for in vivo experiments

      Stachowski, G.M.; Bauer, C.; Waurisch, C.; Bargheer, D.; Nielsen, P.; Heeren, J.; Hickey, Stephen G.; Eychmüller, A. (2014-12-10)
      During the last decades of nanoparticles research, many nanomaterials have been developed for applications in the field of bio-labelling. For the visualization of transport processes in the body, organs and cells, luminescent quantum dots (QDs) make for highly useful diagnostic tools. However, intercellular routes, bio-distribution, metabolism during degradation or quantification of the excretion of nanoparticles, and the study of the biological response to the QDs themselves are areas which to date have not been fully investigated. In order to aid in addressing those issues, CdSe/CdS/ZnS QDs were radioactively labelled, which allows quantification of the QD concentration in the whole body or in ex vivo samples by gamma-counting. However, the synthesis of radioactively labelled QDs is not trivial since the coating process must be completely adapted, and material availability, security and avoidance of radioactive waste must be considered. In this contribution, the coating of CdSe/CdS QDs with a radioactive (65)ZnS shell using a modified, operator-safe, SILAR procedure is presented. Under UV illumination, no difference in the photoluminescence of the radioactive and non-radioactive CdSe/CdS/ZnS colloidal solutions was observed. Furthermore, a down-scaled synthesis for the production of very small batches of 5 nmol QDs without loss in the fluorescence quality was developed. Subsequently, the radio-labelled QDs were phase transferred by encapsulation into an amphiphilic polymer. gamma-counting of the radioactivity provided confirmation of the successful labelling and phase transfer of the QDs.
    • Synthesis of some cryptolepine analogues, assessment of their antimalarial and cytotoxic activities, and consideration of their antimalarial mode of action.

      Wright, Colin W.; Onyeibor, O.; Phillips, Roger M.; Shnyder, Steven D.; Croft, S.L.; Dodson, Hilary I. (2005)
      A series of analogues of cryptolepine (1) have been synthesized and evaluated for their in vitro antiplasmodial and cytotoxic properties. The IC50 values of several compounds (11a, 11k¿m, 11o, 13) against Plasmodium falciparum (strain K1) were <0.1 ¿M, 5¿10-fold lower than that of 1 but their cytotoxicities were only 2¿4 times greater than that of 1. Compounds with a halogen in the quinoline ring and a halogen or a nitro group in the indole ring have enhanced antiplasmodial activity. In mice infected with P. berghei, the 7-bromo-2-chloro (11k) and 2-bromo-7-nitro (13) derivatives of 1 suppressed parasitemia by >90% at doses of 25 mg kg-1 day-1 with no apparent toxicity to the mice. 2,7-Dibromocryptolepine (15) was evaluated at several dose levels, and a dose-dependent suppression of parasitemia was seen (ED90 = 21.6 mg kg-1 day-1). The antimalarial mode of action of 1 appears to be similar to that of chloroquine and involves the inhibition of hemozoin formation. A number of analogues were assessed for their effects on the inhibition of ß-hematin (hemozoin) formation, and the results were compared with their antiplasmodial activities having taken account of their predicted accumulation into the acidic parasite food vacuole. No correlation was seen (r2 = 0.0781) suggesting that the potent antimalarial activity of compounds such as 15 involves other mechanisms in addition to the inhibition of hemozoin formation.
    • Synthesis of sulfonamide-based ynamides and ynamines in water

      Zhao, L.; Yang, H.; Li, R.; Tao, Y.; Guo, X-F.; Anderson, E.A.; Whiting, A.; Wu, Na (Anna) (2021-01)
      Ynamides, though relatively more stable than ynamines, are still moisture-sensitive and prone to hydration especially under acidic and heating conditions. Here we report an environmentally benign, robust protocol to synthesize sulfonamide-based ynamides and arylynamines via Sonogashira coupling reactions in water, using a readily available quaternary ammonium salt as the surfactant.
    • Synthesis of the originally proposed structure of elatenyne and an enyne from Laurencia majuscula

      Sheldrake, Helen M.; Jamieson, C.; Pascu, S.I.; Burton, J.W. (20/12/2009)
      A bidirectional synthesis of the originally proposed structures for the natural products elatenyne and a chloroenyne from Laurencia majuscula is described along with a reassessment of the structures of the halogenated enynes based upon a 13C NMR chemical shift/structure correlation
    • Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal–antiplasmodial activity.

      Sola, I.; Castellà, S.; Viayna, E.; Galdeano, C.; Taylor, M.C.; Gbedema, Stephen Y.; Pérez, B.; Clos, M.V.; Jones, D.C.; Fairlamb, A.H.; et al. (2015-08)
      Dual submicromolar trypanocidal–antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.
    • Synthesis, characterisation, and in vitro anticancer activity of catalytically active indole-based half-sandwich complexes

      Soldevila-Barreda, Joan J.; Fawibe, K.B.; Azmanova, Maria; Rafols, Laia; Pitto-Barry, Anaïs; Eke, U.B.; Barry, Nicolas P.E. (2020-10-03)
      The synthesis, characterisation and evaluation of the in vitro cytotoxicity of four indole-based half-sandwich metal complexes towards two ovarian cancer cell lines (A2780 and A2780cisR) and one normal prostate cell line (PNT2) are presented herein. Although capable of inducing catalytic oxidation of NADH and able to reduce NAD+ with high turnover frequencies, in cells and in the presence of sodium formate, these complexes also strongly interact with biomolecules such as glutathione. This work highlights that efficient out-of-cells catalytic activity might lead to higher reactivity towards biomolecules, thus inhibiting the in-cells catalytic processes.