Brendan Twamley

Synthesis and Biochemical Evaluation of 3-Phenoxy-1,4-diarylazetidin-2-ones as Tubulin-Targeting Antitumor Agents

Structure-activity relationships for a series of 3-phenoxy-1,4-diarylazetidin-2-ones were investigated, leading to the discovery of a number of potent antiproliferative compounds, including trans-4-(3-hydroxy-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (78b) and trans-4-(3-amino-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (90b). X-ray crystallography studies indicate the potential importance of the torsional angle between the 1-phenyl A ring and 4-phenyl B ring for potent antiproliferative activity and that a trans configuration between the 3-phenoxy and 4-phenyl rings is generally optimal. These compounds displayed IC50 values of 38 and 19 nM, respectively, in MCF-7 breast cancer cells, inhibited the polymerization of isolated tubulin in vitro, disrupted the microtubular structure in MCF-7 cells as visualized by confocal microscopy, and caused G2/M arrest and apoptosis. Compound 90b possessed a mean GI50 value of 22 nM in the NCI60 cell line screen, displayed minimal cytotoxicity, and was shown to interact at the colchicine-binding site on β-tubulin. Phosphate and amino acid prodrugs of both 78b and 90b were synthesized, of which the alanine amide 102b retained potency and is a promising candidate for further clinical development.

Novel acetylene-linked di-cobalt and tetra-cobalt carbonyl clusters

Abstract {Co2(CO)6} groups were attached to p-diethynylbenzene-based acetylenes giving complexes of general formula [{Co2(CO)6}(μ2-η2:2-RC2C6H4C2R′)] ((4): R=R′=H; (4a): R=SiMe3, R′=H; (4b): R=R′=SiMe3); [{Co2(CO)6}2(μ4-η2:2:2:2-RC2C6H4C2R′)] ((3): R=R′=H; (3a): R=SiMe3, R′=H; (3b): R=R′=SiMe3); [{Co2(CO)6}4(μ8-η2:2:2:2:2:2:2:2-R2C6H4C2C2C6H4C2R)]((5): R=H; (5b):R=SiMe3). The addition of Co4(CO)12 to p-diethynylbenzene and to 4 was also investigated, producing [{Co4(CO)8(μ-CO)2}(μ4-HC2C6H4C2H)] (6) and [{Co2(CO)6}{(Co4(CO)8(μ-CO)2}(μ8-HC2C6H4C2H)] (7). The syntheses of the acetylenic derivatives of C60 [(trimethylsilyl)ethynyl]hydrofullerene[60] (8a) and (phenylethynyl)hydrofullerene[60] (9) and the new ligand [(trimethylsilyl)diethynylbenzene]hydrofullerene[60] (10a) were performed and the resulting acetylenes were reacted with dicobaltoctacarbonyl giving the corresponding complexes [(trimethylsilyl)(dicobalthexacarbonyl)ethynyl]hydrofullerene[60] (11a), (phenylethynyl)(dicobalthexacarbonyl)hydrofullerene[60] (12) and [(trimethylsilyl)bis(dicobalthexacarbonyl)diethynylbenzene] (13a). The reaction of 1-bromo-3,5-diethynylbenzene and 1,3,5-triethynylbenzene with dicobaltoctacarbonyl resulted in the formation of [HC2{Co2(CO)6}]2C6H2Br (16) and [HC2{Co2(CO)6}]2C6H3 (15) as expected. Crystals of 3a, 3b, 4, 4b, 15 and 16 suitable for single-crystal X-ray diffraction were grown and the molecular structures of these compounds are discussed.

A novel dual-functioning ruthenium(II)-arene complex of an anti-microbial ciprofloxacin derivative - Anti-proliferative and anti-microbial activity.

7-(4-(Decanoyl)piperazin-1-yl)-ciprofloxacin, CipA, (1) which is an analogue of the antibiotic ciprofloxacin, and its ruthenium(II) complex [Ru(η(6)-p-cymene)(CipA-H)Cl], (2) have been synthesised and the x-ray crystal structures of 1·1.3H2O·0.6CH3OH and 2·CH3OH·0.5H2O determined. The complex adopts a typical pseudo-octahedral piano-stool geometry, with Ru(II) π-bonded to the p-cymene ring and σ-bonded to a chloride and two oxygen atoms of the chelated fluoroquinolone ligand. The complex is highly cytotoxic in the low μM range and is as potent as the clinical drug cisplatin against the human cancer cell lines A2780, A549, HCT116, and PC3. It is also highly cytotoxic against cisplatin- and oxaliplatin-resistant cell lines suggesting a different mechanism of action. The complex also retained low μM cytotoxicity against the human colon cancer cell line HCT116p53 in which the tumour suppressor p53 had been knocked out, suggesting that the potent anti-proliferative properties associated with this complex are independent of the status of p53 (in contrast to cisplatin). The complex also retained moderate anti-bacterial activity in two Escherichia coli, a laboratory strain and a clinical isolate resistant to first, second and third generation β-lactam antibiotics.

Fabrication and characterisation of gold nano-particle modified polymer monoliths for flow-through catalytic reactions and their application in the reduction of hexacyanoferrate

AbstractPolymer monoliths in capillary (100xa0μm i.d.) and polypropylene pipette tip formats (vol: 20xa0μL) were modified with gold nano-particles (AuNP) and subsequently used for flow-through catalytic reactions. Specifically, methacrylate monoliths were modified with amine-reactive monomers using a two-step photografting method and then reacted with ethylenediamine to provide amine attachment sites for the subsequent immobilisation of 4xa0nm, 7xa0nm or 16xa0nm AuNP. This was achieved by flushing colloidal suspensions of gold nano-particles through each aminated polymer monolith which resulted in a multi-point covalent attachment of gold via the lone pair of electrons on the nitrogen of the free amine groups. Field emission scanning electron microscopy and scanning capacitively coupled conductivity detection was used to characterise the surface coverage of AuNP on the monoliths. The catalytic activity of AuNP immobilised on the polymer monoliths in both formats was then demonstrated using the reduction of Fe(III) to Fe(II) by sodium borohydride as a model reaction by monitoring the reduction in absorbance of the hexacyanoferrate (ІІІ) complex at 420xa0nm. Catalytic activity was significantly enhanced on monoliths modified with smaller AuNP with almost complete reduction (95xa0%) observed when using monoliths agglomerated with 7xa0nm AuNPs.n FigureGold nano-particles were immobilised upon a porous polymer monolith and used for the micro-scale catalytic reduction of Fe (III) to Fe (II) in flow-through mode

Characterization of a novel and potentially lethal designer drug (±)‐cis‐para‐methyl‐4‐methylaminorex (4,4'‐DMAR, or ‘Serotoni’)

During the second half of 2013, a total of 26 deaths involving para-methyl-4-methylaminorex (4,4-DMAR) were reported to the European Monitoring Centre for Drugs and Drug Addiction. While aminorex and 4-methylaminorex (4-MAR) are known psychostimulants, nothing is known about the comparatively new para-methyl analog. Analytical characterization of two independent samples obtained from online vendors confirmed the presence of the (±)-cis isomer that also appeared to be associated with at least 18 of the 26 deaths. Extensive characterizations included crystal structure analysis, single, tandem, and high-resolution mass spectrometry, liquid and gas chromatography, and nuclear magnetic resonance spectroscopy. For the work described here, both the (±)-cis and (±)-trans racemates were also synthesized, confirming that the differentiation between these two forms was straight-forward. Monoamine transporter activity was studied using rat brain synaptosomes which included the comparison with d-amphetamine, aminorex and (±)-cis-4-MAR. (±)-cis-4,4-DMAR was a potent, efficacious substrate-type releaser at transporters for dopamine, norepinephrine and serotonin with EC50 values of 8.6 ± 1.1 nM (DAT), 26.9 ± 5.9 nM (NET) and 18.5 ± 2.8 nM (SERT), respectively. The potency of (±)-cis-4,4-DMAR at DAT and NET rivalled that of other psychomotor stimulant drugs like d-amphetamine and aminorex. However, (±)-cis-4,4-DMAR had much more potent actions at SERT and activity at SERT varied more than 100-fold across the four drugs. The potent releasing activity of (±)-cis-4,4-DMAR at all three monoamine transporters predicts a potential for serious side-effects such as psychotic symptoms, agitation, hyperthermia and cardiovascular stimulation, especially after high-dose exposure or following combination with other psychostimulants.

Highly Efficient Triplet Photosensitizers: A Systematic Approach to the Application of IrIII Complexes containing Extended Phenanthrolines

A series of Ir(III) complexes, based on 1,10-phenanthroline featuring aryl acetylene chromophores, were prepared and investigated as triplet photosensitizers. The complexes were synthesized by Sonogashira cross-coupling reactions using a chemistry-on-the-complex method. The absorption properties and luminescence lifetimes were successfully tuned by controlling the number and type of light-harvesting group. Intense UV/Vis absorption was observed for the Ir(III) complexes with two light-harvesting groups at the 3- and 8-positions of the phenanthroline. The asymmetric Ir(III) complex (with a triphenylamine (TPA) and a pyrene moiety attached) exhibited the longest lifetime. Red emission was observed for all the complexes in deaerated solutions at room temperature. Their emission at low temperature (77u2005K) and nanosecond time-resolved transient difference absorption spectra revealed the origin of their triplet excited states. The singlet-oxygen ((1) O2 ) sensitization and triplet-triplet annihilation (TTA)-based upconversion were explored. Highly efficient TTA upconversion (ΦUC =28.1u2009%) and (1) O2 sensitization (ΦΔ =97.0u2009%) were achieved for the asymmetric Ir(III) complex, which showed intense absorption in the visible region (λabs =482u2005nm, ϵ=50900u2009m(-1) u2009cm(-1) ) and had a long-lived triplet excited state (53.3u2005μs at RT).

Iridium(III) Complexes Bearing Pyrene-Functionalized 1,10-Phenanthroline Ligands as Highly Efficient Sensitizers for Triplet–Triplet Annihilation Upconversion

Chemistry-on-the-complex synthetic methods have allowed the selective addition of 1-ethynylpyrene appendages to the 3-, 5-, 3,8- and 5,6-positions of IrIII -coordinated 1,10-phenanthroline via Sonogashira cross-coupling. The resulting suite of complexes has given rise to the first rationalization of their absorption and emission properties as a function of the number and position of the pyrene moieties. Strong absorption in the visible region (e.g. 3,8-substituted Ir-3: λabs =481u2005nm, ϵ=52u2009400u2009m-1 u2009cm-1 ) and long-lived triplet excited states (e.g. 5-substituted Ir-2: τT =367.7u2005μs) were observed for the complexes in deaerated CH2 Cl2 . On testing the series as triplet sensitizers for triplet-triplet annihilation upconversion, those IrIII complexes bearing pyrenyl appendages at the 3- and 3,8-positions (Ir-1, Ir-3) were found to give optimal upconversion quantum yields (30.2u2009% and 31.6u2009% respectively).

Piperlongumine (piplartine) and analogues: Antiproliferative microtubule-destabilising agents

Piperlongumine (piplartine, 1) is a small molecule alkaloid that is receiving intense interest due to its antiproliferative and anticancer activities. We investigated the effects of 1 on tubulin and microtubules. Using both an isolated tubulin assay, and a combination of sedimentation and western blotting, we demonstrated that 1 is a tubulin-destabilising agent. This result was confirmed by immunofluorescence and confocal microscopy, which showed that microtubules in MCF-7 breast cancer cells were depolymerized when treated with 1. We synthesised a number of analogues of 1 to explore structure-activity relationships. Compound 13 had the best cytotoxic profile of this series, showing potent effects in human breast carcinoma MCF-7xa0cells whilst being relatively non-toxic to non-tumorigenic MCF-10a cells. Thesexa0compounds will be further developed as potential clinical candidates for the treatment of breast cancer.

New synthetic pathways to the preparation of near-blue emitting heteroleptic Ir(III)N6 coordinated compounds with microsecond lifetimes

A high yield synthetic route for the preparation of N6 coordinated heteroleptic Ir(III) complexes using bidentate polypyridyl type ligands is described. The complexes are near-blue emitters and show microsecond emission lifetimes, high emission quantum yields and have two quasi-reversible reduction processes between -1.0 and -1.3 V vs. Ag/AgCl.

Agglomerated polymer monoliths with bimetallic nano-particles as flow-through micro-reactors

AbstractPolymer monoliths in capillary format have been prepared as solid supports for the immobilisation of platinum/palladium bimetallic nano-flowers. Optimum surface coverage of nano-flowers was realised by photografting the monoliths with vinyl azlactone followed by amination with ethylenediamine prior to nano-particle immobilisation. Field emission SEM imaging was used as a characterisation tool for evaluating nano-particle coverage, together with BET surface area analysis to probe the effect of nano-particle immobilisation upon monolith morphology. Ion exchange chromatography was also used to confirm the nature of the covalent attachment of nano-flowers on the monolithic surface. In addition, EDX and ICP analyses were used to quantify platinum and palladium on modified polymer monoliths. Finally the catalytic properties of immobilised bimetallic Pd/Pt nano-flowers were evaluated in flow-through mode, exploiting the porous interconnected flow-paths present in the prepared monoliths (pore diameter~1–2xa0μm). Specifically, the reduction of Fe (III) to Fe (II) and the oxidation of NADH to NAD+ were selected as model redox reactions. The use of a porous polymer monolith as an immobilisation substrate (rather than aminated micro-spheres) eliminated the need for a centrifugation step after the reaction.n FigurePlatinum/palladium bimetallic nanoflowers are immobilised on a porous polymer monolith for use as a flow-through microreactor