Publications by year
In Press
Curnow A, Anayo L, Magnussen A, Perry A, Wood M (In Press). AN EXPERIMENTAL INVESTIGATION OF a NOVEL IRON CHELATING PROTOPORPHYRIN IX PRODRUG FOR THE ENHANCEMENT OF PHOTODYNAMIC THERAPY. Lasers in Surgery and Medicine
Wood ME, Alexander BE, Coles SJ, Fox BC, Khan TF, Maliszewski J, Perry A, Pitak MB, Whiteman M (In Press). investigating the generation of hydrogen sulfide from the phosphonamidodithioate slow-release donor GYY4137. MedChemComm
2022
Hughes‐Whiffing CA, Perry A (2022). Three Complementary One‐Pot Four‐Component Reaction Sequences for Rapid, General and Direct Spiropyran Synthesis. European Journal of Organic Chemistry, 26(2).
2021
Curnow A, Magnussen A, Reburn C, Perry A, Wood M (2021). Experimental investigation of a combinational iron chelating. protoporphyrin IX prodrug for fluorescence detection and photodynamic therapy. Lasers in Medical Science
Hughes-Whiffing CA, Perry A (2021). One-pot, three-component Fischer indolisation–<i>N</i>-alkylation for rapid synthesis of 1,2,3-trisubstituted indoles.
Organic & Biomolecular Chemistry,
19(3), 627-634.
Abstract:
One-pot, three-component Fischer indolisation–N-alkylation for rapid synthesis of 1,2,3-trisubstituted indoles
One-pot Fischer indolisation indole N-alkylation enables straightforward, rapid synthesis of structurally-diverse 1,2,3-trisubstituted indoles from simple, widely-available precursors.
Abstract.
2020
Swinson H, Perry A (2020). Three-component spiropyran synthesis via tandem alkylation-condensation.
Tetrahedron,
76(23).
Abstract:
Three-component spiropyran synthesis via tandem alkylation-condensation
A catalyst-free, three-component alkylation-condensation cascade for spiropyran synthesis has been developed, using readily available building blocks (indoles, alkyl halides, salicylaldehydes) and environmentally benign solvents (water, ethanol). A cascade approach enables this sequence to proceed under mild conditions which, in turn, promote broad substrate tolerance and operational simplicity. Consequently, we have demonstrated the utility of this process in the synthesis of 25 structurally-diverse spiropyrans, incorporating useful functionality across the spiropyran framework, and on multi-gram scale.
Abstract.
2019
Reburn C, Anayo L, Magnussen A, Perry A, Wood M, Curnow A (2019). Experimental findings utilising a new iron chelating ALA prodrug to enhance protoporphyrin IX-induced photodynamic therapy.
Abstract:
Experimental findings utilising a new iron chelating ALA prodrug to enhance protoporphyrin IX-induced photodynamic therapy
Abstract.
Curnow A, Perry A, Wood M (2019). Improving in vitro photodynamic therapy through the development of a novel iron chelating aminolaevulinic acid prodrug.
Photodiagnosis Photodyn Ther,
25, 157-165.
Abstract:
Improving in vitro photodynamic therapy through the development of a novel iron chelating aminolaevulinic acid prodrug.
BACKGROUND: Photodynamic therapy (PDT) is a light activated drug therapy that can be used to treat a number of cancers and precancers. It is particularly useful in its topical form in dermatology but improvement of efficacy is required to widen its application. METHODS: an ester between aminolaevulinic acid (ALA) and CP94 was synthesised (AP2-18) and experimentally evaluated to determine whether protoporphyrin IX (PpIX)-induced PDT effectiveness could be improved. A biological evaluation of AP2-18 was conducted in cultured human primary cells with both PpIX fluorescence and cell viability (as determined via the neutral red assay) being assessed in comparison to the PpIX prodrugs normally utilised in clinical practice (aminolaevulinic acid (ALA) or its methyl ester (MAL)) either administered alone or with the comparator iron chelator, CP94. RESULTS: No significant dark toxicity was observed in human lung fibroblasts but AP2-18 significantly increased PpIX accumulation above and beyond that achieved with ALA or MAL administration +/- CP94 in both human dermal fibroblasts and epithelial squamous carcinoma cells. On light exposure, the combined hydroxypyridinone iron chelating ALA prodrug AP2-18 generated significantly greater cytotoxicity than any of the other treatment parameters investigated when the lowest concentration (250 μM) was employed. CONCLUSIONS: Newly synthesised AP2-18 is therefore concluded to be an efficacious prodrug for PpIX-induced PDT in these dermatologically relevant human cells, achieving enhanced effects at lower concentrations than currently possible with existing pharmaceuticals.
Abstract.
Author URL.
Perry A (2019). New mechanism, new chromophore: investigating the electrophilic behaviour of styrylindolium dyes.
Org Biomol Chem,
17(19), 4825-4834.
Abstract:
New mechanism, new chromophore: investigating the electrophilic behaviour of styrylindolium dyes.
To inform the design of future merocyanine-based sensors for nucleophilic analytes, a range of model styrylindolium salts were synthesised, and their behaviour towards cyanide, methanethiolate and sulfide was examined using spectroscopic techniques. In the majority of cases, standard 1,2- and 1,4-nucleophilic additions predominated; however, 4-nitrostyrylindolium salts underwent an unexpected dearomatising 1,8-addition with sulfur-centred nucleophiles. The enamine triene products thus produced display useful optical properties and provide a platform for novel sensor design, and the unusual 1,8-reaction pathway enables synthesis of novel molecular architecture.
Abstract.
Author URL.
2018
Brown AR, Green J, Moreman J, Gunnarsson L, Mourabit S, Ball J, Winter M, Trznadel M, Correia A, Hacker C, et al (2018). Cardiovascular Effects and Molecular Mechanisms of Bisphenol a and its Metabolite MBP in Zebrafish. Environmental Science and Technology
Moreman J, Takesono A, Trznadel M, Winter MJ, Perry A, Wood ME, Rogers NJ, Kudoh T, Tyler CR (2018). Estrogenic Mechanisms and Cardiac Responses Following Early Life Exposure to Bisphenol a (BPA) and its Metabolite 4-Methyl-2,4-bis( p-hydroxyphenyl)pent-1-ene (MBP) in Zebrafish.
Environ Sci Technol,
52(11), 6656-6665.
Abstract:
Estrogenic Mechanisms and Cardiac Responses Following Early Life Exposure to Bisphenol a (BPA) and its Metabolite 4-Methyl-2,4-bis( p-hydroxyphenyl)pent-1-ene (MBP) in Zebrafish.
Environmental exposure to Bisphenol a (BPA) has been associated with a range of adverse health effects, including on the cardiovascular system in humans. Lack of agreement on its mechanism(s) of action likely stem from comparisons between in vivo and in vitro test systems and potential multiple effects pathways. In rodents, in vivo, metabolic activation of BPA produces 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), which is reported to be up to 1000 times more potent as an estrogen than BPA. We investigated the estrogenic effects and estrogen receptor signaling pathway(s) of BPA and MBP following early life exposure using a transgenic, estrogen responsive (ERE-TG) zebrafish and a targeted morpholino approach to knockdown the three fish estrogen receptor (ER) subtypes. The functional consequences of BPA exposure on the cardiovascular system of zebrafish larvae were also examined. The heart atrioventricular valves and the bulbus arteriosus were primary target tissues for both BPA and MBP in the ERE-TG zebrafish, and MBP was approximately 1000-fold more potent than BPA as an estrogen in these tissues. Estrogen receptor knockdown with morpholinos indicated that the estrogenic responses in the heart for both BPA and MBP were mediated via an estrogen receptor 1 (esr1) dependent pathway. At the highest BPA concentration tested (2500 μg/L), alterations in the atrial:ventricular beat ratio indicated a functional impact on the heart of 5 days post fertilization (dpf) larvae, and there was also a significantly reduced heart rate in these larvae at 14 dpf. Our findings indicate that some of the reported adverse effects on heart function associated with BPA exposure (in mammals) may act through an estrogenic mechanism, but that fish are unlikely to be susceptible to adverse effects on heart development for environmentally relevant exposures.
Abstract.
Author URL.
Perry A, Davis K, West L (2018). Synthesis of stereochemically-biased spiropyrans by microwave-promoted, one-pot alkylation-condensation.
Organic and Biomolecular Chemistry,
16(39), 7245-7254.
Abstract:
Synthesis of stereochemically-biased spiropyrans by microwave-promoted, one-pot alkylation-condensation
© 2018 the Royal Society of Chemistry. A microwave-assisted, two-step, one-pot synthesis of spiropyrans has been developed. This process was used to synthesise a range of sterically-congested spiropyrans from readily available precursors, employing environmentally benign solvents. The unusual substituent pattern possessed by these structures has been shown to influence the stereoselectivity of spiropyran ring-closure.
Abstract.
2017
Waters A, Torregrossa R, Gero D, Perry A, Wood ME, Whiteman M (2017). RT01, a Novel Derivative of the Mitochondria-targeted Hydrogen Sulfide Donor AP39, Reversed Hyperglycaemia-induced Mitochondrial Dysfunction in Murine Brain Microvascular Endothelial Cells.
Author URL.
Perry A, Kousseff CJ (2017). Synthesis and metal binding properties of N-alkylcarboxyspiropyrans.
Beilstein Journal of Organic Chemistry,
13, 1542-1550.
Abstract:
Synthesis and metal binding properties of N-alkylcarboxyspiropyrans
Spiropyrans bearing an N-alkylcarboxylate tether are a common structure in dynamic, photoactive materials and serve as colourimetric/fluorimetric cation receptors. In this study, we describe an efficient synthesis of spiropyrans with 2–12 carbon atom alkylcarboxylate substituents, and a systematic analysis of their interactions with metal cations using 1H NMR and UV-visible spectroscopy. All N-alkylcarboxyspiropyrans in this study displayed a strong preference for binding divalent metal cations and a modest increase in M2+ binding affinity correlated with increased alkycarboxylate tether length.
Abstract.
2016
Perry A, Miles D (2016). An off-the-shelf sensor for colourimetric detection of sulfide.
Tetrahedron Letters,
57(51), 5788-5793.
Abstract:
An off-the-shelf sensor for colourimetric detection of sulfide
The cheap, accessible spiropyran nitroBIPS is a sensitive, selective colourimetric sensor for quantitative determination of sulfide in aqueous media at neutral pH.
Abstract.
Gero D, Torregrossa R, Waters A, Perry A, Wood ME, Whiteman M (2016). Mitochondria-Targeted Hydrogen Sulfide Donors Protect Microvascular Endothelial Cells from Hyperglycaemia-Induced Metabolic Changes and Oxidative Damage.
Author URL.
Gerő D, Torregrossa R, Perry A, Waters A, Le-Trionnaire S, Whatmore JL, Wood M, Whiteman M (2016). The novel mitochondria-targeted hydrogen sulfide (H2S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro.
Pharmacol Res,
113(Pt A), 186-198.
Abstract:
The novel mitochondria-targeted hydrogen sulfide (H2S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro.
The development of diabetic vascular complications is initiated, at least in part, by mitochondrial reactive oxygen species (ROS) production in endothelial cells. Hyperglycemia induces superoxide production in the mitochondria and initiates changes in the mitochondrial membrane potential that leads to mitochondrial dysfunction. Hydrogen sulfide (H2S) supplementation has been shown to reduce the mitochondrial oxidant production and shows efficacy against diabetic vascular damage in vivo. However, the half-life of H2S is very short and it is not specific for the mitochondria. We have therefore evaluated two novel mitochondria-targeted anethole dithiolethione and hydroxythiobenzamide H2S donors (AP39 and AP123 respectively) at preventing hyperglycemia-induced oxidative stress and metabolic changes in microvascular endothelial cells in vitro. Hyperglycemia (HG) induced significant increase in the activity of the citric acid cycle and led to elevated mitochondrial membrane potential. Mitochondrial oxidant production was increased and the mitochondrial electron transport decreased in hyperglycemic cells. AP39 and AP123 (30-300nM) decreased HG-induced hyperpolarisation of the mitochondrial membrane and inhibited the mitochondrial oxidant production. Both H2S donors (30-300nM) increased the electron transport at respiratory complex III and improved the cellular metabolism. Targeting H2S to mitochondria retained the cytoprotective effect of H2S against glucose-induced damage in endothelial cells suggesting that the molecular target of H2S action is within the mitochondria. Mitochondrial targeting of H2S also induced >1000-fold increase in the potency of H2S against hyperglycemia-induced injury. The high potency and long-lasting effect elicited by these H2S donors strongly suggests that these compounds could be useful against diabetic vascular complications.
Abstract.
Author URL.
2015
Perry A, Green SJ, Horsell DW, Homett SM, Wood ME (2015). A pyrene-appended spiropyran for selective photo-switchable binding of Zn(II): UV-visible and fluorescence spectroscopy studies of binding and non-covalent attachment to graphene, graphene oxide and carbon nanotubes.
TETRAHEDRON,
71(38), 6776-6783.
Author URL.
Perry A, Green SJ, Horsell DW, Hornett SM, Wood ME (2015). A pyrene-appended spiropyran for selective photo-switchable binding of Zn(II): UV-visible and fluorescence spectroscopy studies of binding and non-covalent attachment to graphene, graphene oxide and carbon nanotubes.
TetrahedronAbstract:
A pyrene-appended spiropyran for selective photo-switchable binding of Zn(II): UV-visible and fluorescence spectroscopy studies of binding and non-covalent attachment to graphene, graphene oxide and carbon nanotubes
Synthesis of photo-switchable, Zn2+ sensitive hybrid materials was achieved by facile non-covalent functionalization of graphene, graphene oxide and carbon nanotubes with a pyrene-appended spiropyran. Solution phase binding studies, using UV-visible and fluorescence spectroscopy, indicated that the pyrene-spiropyran dyad was highly selective for Zn2+ over a range of potentially competitive cations and that binding occurred with 1:1 stoichiometry and a binding constant of K=1.4×104mol-1dm3 at 295K. Zn2+ binding was promoted by UV irradiation or in darkness and reversed upon irradiation with visible light.
Abstract.
Tomasova L, Pavlovicova M, Malekova L, Misak A, Kristek F, Grman M, Cacanyiova S, Tomasek M, Tomaskova Z, Perry A, et al (2015). Effects of AP39, a novel triphenylphosphonium derivatised anethole dithiolethione hydrogen sulfide donor, on rat haemodynamic parameters and chloride and calcium Ca<inf>v</inf>3 and RyR2 channels.
Nitric Oxide - Biology and Chemistry,
46, 131-144.
Abstract:
Effects of AP39, a novel triphenylphosphonium derivatised anethole dithiolethione hydrogen sulfide donor, on rat haemodynamic parameters and chloride and calcium Cav3 and RyR2 channels
H2S donor molecules have the potential to be viable therapeutic agents. The aim of this current study was (i) to investigate the effects of a novel triphenylphosphonium derivatised dithiolethione (AP39), in the presence and absence of reduced nitric oxide bioavailability and (ii) to determine the effects of AP39 on myocardial membrane channels; CaV3, RyR2 and Cl-. Normotensive, L-NAME- or phenylephrine-treated rats were administered Na2S, AP39 or control compounds (AP219 and ADT-OH) (0.25-1μmol kg-1 i.v.) and haemodynamic parameters measured. The involvement of membrane channels T-type Ca2+ channels CaV3.1, CaV3.2 and CaV3.3 as well as Ca2+ ryanodine (RyR2) and Cl- single channels derived from rat heart sarcoplasmic reticulum were also investigated. In anaesthetised Wistar rats, AP39 (0.25-1μmol kg-1 i.v) transiently decreased blood pressure, heart rate and pulse wave velocity, whereas AP219 and ADT-OH and Na2S had no significant effect. In L-NAME treated rats, AP39 significantly lowered systolic blood pressure for a prolonged period, decreased heart rate and arterial stiffness. In electrophysiological studies, AP39 significantly inhibited Ca2+ current through all three CaV3 channels. AP39 decreased RyR2 channels activity and increased conductance and mean open time of Cl- channels. This study suggests that AP39 may offer a novel therapeutic opportunity in conditions whereby •NO and H2S bioavailability are deficient such as hypertension, and that CaV3, RyR2 and Cl- cardiac membrane channels might be involved in its biological actions.
Abstract.
Tomasova L, Pavlovicova M, Malekova L, Misak A, Kristek F, Grman M, Cacanyiova S, Tomasek M, Tomaskova Z, Perry A, et al (2015). Effects of AP39, a novel triphenylphosphonium derivatised anethole dithiolethione hydrogen sulfide donor, on rat haemodynamic parameters and chloride and calcium Cav3 and RyR2 channels.
Nitric Oxide,
46, 131-144.
Abstract:
Effects of AP39, a novel triphenylphosphonium derivatised anethole dithiolethione hydrogen sulfide donor, on rat haemodynamic parameters and chloride and calcium Cav3 and RyR2 channels.
H2S donor molecules have the potential to be viable therapeutic agents. The aim of this current study was (i) to investigate the effects of a novel triphenylphosphonium derivatised dithiolethione (AP39), in the presence and absence of reduced nitric oxide bioavailability and (ii) to determine the effects of AP39 on myocardial membrane channels; CaV3, RyR2 and Cl(-). Normotensive, L-NAME- or phenylephrine-treated rats were administered Na2S, AP39 or control compounds (AP219 and ADT-OH) (0.25-1 µmol kg(-1)i.v.) and haemodynamic parameters measured. The involvement of membrane channels T-type Ca(2+) channels CaV3.1, CaV3.2 and CaV3.3 as well as Ca(2+) ryanodine (RyR2) and Cl(-) single channels derived from rat heart sarcoplasmic reticulum were also investigated. In anaesthetised Wistar rats, AP39 (0.25-1 µmol kg(-1) i.v) transiently decreased blood pressure, heart rate and pulse wave velocity, whereas AP219 and ADT-OH and Na2S had no significant effect. In L-NAME treated rats, AP39 significantly lowered systolic blood pressure for a prolonged period, decreased heart rate and arterial stiffness. In electrophysiological studies, AP39 significantly inhibited Ca(2+) current through all three CaV3 channels. AP39 decreased RyR2 channels activity and increased conductance and mean open time of Cl(-) channels. This study suggests that AP39 may offer a novel therapeutic opportunity in conditions whereby (•)NO and H2S bioavailability are deficient such as hypertension, and that CaV3, RyR2 and Cl(-) cardiac membrane channels might be involved in its biological actions.
Abstract.
Author URL.
Alexander BE, Coles SJ, Khan TF, Maliszewsi J, Perry A, Pitak MP, Whiteman M, Wood ME (2015). Investigating the generation of hydrogen sulphide from the phosphinodithioate slow-release donor GYY4137: Novel products and experimental tools.
Author URL.
Whiteman M, Perry A, Zhou Z, Bucci M, Papapetropoulos A, Cirino G, Wood ME (2015). Phosphinodithioate and Phosphoramidodithioate Hydrogen Sulfide Donors.
Handb Exp Pharmacol,
230, 337-363.
Abstract:
Phosphinodithioate and Phosphoramidodithioate Hydrogen Sulfide Donors.
Hydrogen sulfide is rapidly emerging as a key physiological mediator and potential therapeutic tool in numerous areas such as acute and chronic inflammation, neurodegenerative and cardiovascular disease, diabetes, obesity and cancer. However, the vast majority of the published studies have employed crude sulfide salts such as sodium hydrosulfide (NaSH) and sodium sulfide (Na2S) as H2S "donors" to generate H2S. Although these salts are cheap, readily available and easy to use, H2S generated from them occurs as an instantaneous and pH-dependent dissociation, whereas endogenous H2S synthesis from the enzymes cystathionine γ-lyase, cystathionine-β-synthase and 3-mercaptopyruvate sulfurtransferase is a slow and sustained process. Furthermore, sulfide salts are frequently used at concentrations (e.g. 100 μM to 10 mM) far in excess of the levels of H2S reported in vivo (nM to low μM). For the therapeutic potential of H2S is to be properly harnessed, pharmacological agents which generate H2S in a physiological manner and deliver physiologically relevant concentrations are needed. The phosphorodithioate GYY4137 has been proposed as "slow-release" H2S donors and has shown promising efficacy in cellular and animal model diseases such as hypertension, sepsis, atherosclerosis, neonatal lung injury and cancer. However, H2S generation from GYY4137 is inefficient necessitating its use at high concentrations/doses. However, structural modification of the phosphorodithioate core has led to compounds (e.g. AP67 and AP105) with accelerated rates of H2S generation and enhanced biological activity. In this review, the therapeutic potential and limitations of GYY4137 and related phosphorodithioate derivatives are discussed.
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Author URL.
2014
Hurst TE, Gorman RM, Drouhin P, Perry A, Taylor RJK (2014). A direct C-H/Ar-H coupling approach to oxindoles, thio-oxindoles, 3,4-dihydro-1 H-quinolin-2-ones, and 1,2,3,4-tetrahydroquinolines.
Chemistry (Weinheim an der Bergstrasse, Germany),
20(43), 14063-14073.
Abstract:
A direct C-H/Ar-H coupling approach to oxindoles, thio-oxindoles, 3,4-dihydro-1 H-quinolin-2-ones, and 1,2,3,4-tetrahydroquinolines
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.A copper(II)-catalysed approach to oxindoles, thio-oxindoles, 3,4-dihydro-1H-quinolin-2-ones, and 1,2,3,4-tetrahydroquinolines via formal C-H, Ar-H coupling is described. In a new variant, copper(II) 2-ethylhexanoate has been identified as an inexpensive and efficient catalyst for this transformation, which utilises atmospheric oxygen as the re-oxidant.
Abstract.
Hurst TE, Gorman RM, Drouhin P, Perry A, Taylor RJK (2014). A direct C-H/Ar-H coupling approach to oxindoles, thio-oxindoles, 3,4-dihydro-1 H-quinolin-2-ones, and 1,2,3,4-tetrahydroquinolines.
Chemistry,
20(43), 14063-14073.
Abstract:
A direct C-H/Ar-H coupling approach to oxindoles, thio-oxindoles, 3,4-dihydro-1 H-quinolin-2-ones, and 1,2,3,4-tetrahydroquinolines.
A copper(II)-catalysed approach to oxindoles, thio-oxindoles, 3,4-dihydro-1H-quinolin-2-ones, and 1,2,3,4-tetrahydroquinolines via formal C-H, Ar-H coupling is described. In a new variant, copper(II) 2-ethylhexanoate has been identified as an inexpensive and efficient catalyst for this transformation, which utilises atmospheric oxygen as the re-oxidant.
Abstract.
Author URL.
Szczesny B, Módis K, Yanagi K, Coletta C, Le Trionnaire S, Perry A, Wood ME, Whiteman M, Szabo C (2014). AP39, a novel mitochondria-targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro.
Nitric Oxide - Biology and Chemistry,
41, 120-130.
Abstract:
AP39, a novel mitochondria-targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro
The purpose of the current study was to investigate the effect of the recently synthesized mitochondrially- Targeted H2S donor, AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5yl)phenoxy)decyl) triphenylphosphonium bromide], on bioenergetics, viability, and mitochondrial DNA integrity in bEnd.3 murine microvascular endothelial cells in vitro, under normal conditions, and during oxidative stress. Intracellular H2S was assessed by the fluorescent dye 7-azido-4-methylcoumarin. For the measurement of bioenergetic function, the XF24 Extracellular Flux Analyzer was used. Cell viability was estimated by the combination of the MTT and LDH methods. Oxidative protein modifications were measured by the Oxyblot method. Reactive oxygen species production was monitored by the MitoSOX method. Mitochondrial and nuclear DNA integrity were assayed by the Long Amplicon PCR method. Oxidative stress was induced by addition of glucose oxidase. Addition of AP39 (30-300 nM) to bEnd.3 cells increased intracellular H2S levels, with a preferential response in the mitochondrial regions. AP39 exerted a concentrationdependent effect on mitochondrial activity, which consisted of a stimulation of mitochondrial electron transport and cellular bioenergetic function at lower concentrations (30-100 nM) and an inhibitory effect at the higher concentration of 300 nM. Under oxidative stress conditions induced by glucose oxidase, an increase in oxidative protein modification and an enhancement in MitoSOX oxidation was noted, coupled with an inhibition of cellular bioenergetic function and a reduction in cell viability. AP39 pretreatment attenuated these responses. Glucose oxidase induced a preferential damage to the mitochondrial DNA; AP39 (100 nM) pretreatment protected against it. In conclusion, the current paper documents antioxidant and cytoprotective effects of AP39 under oxidative stress conditions, including a protection against oxidative mitochondrial DNA damage. © 2014 Elsevier Inc. All rights reserved.
Abstract.
Szczesny B, Módis K, Yanagi K, Coletta C, Le Trionnaire S, Perry A, Wood ME, Whiteman M, Szabo C (2014). AP39, a novel mitochondria-targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro.
Nitric Oxide,
41, 120-130.
Abstract:
AP39, a novel mitochondria-targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro.
The purpose of the current study was to investigate the effect of the recently synthesized mitochondrially-targeted H2S donor, AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5yl)phenoxy)decyl) triphenylphosphonium bromide], on bioenergetics, viability, and mitochondrial DNA integrity in bEnd.3 murine microvascular endothelial cells in vitro, under normal conditions, and during oxidative stress. Intracellular H2S was assessed by the fluorescent dye 7-azido-4-methylcoumarin. For the measurement of bioenergetic function, the XF24 Extracellular Flux Analyzer was used. Cell viability was estimated by the combination of the MTT and LDH methods. Oxidative protein modifications were measured by the Oxyblot method. Reactive oxygen species production was monitored by the MitoSOX method. Mitochondrial and nuclear DNA integrity were assayed by the Long Amplicon PCR method. Oxidative stress was induced by addition of glucose oxidase. Addition of AP39 (30-300 nM) to bEnd.3 cells increased intracellular H2S levels, with a preferential response in the mitochondrial regions. AP39 exerted a concentration-dependent effect on mitochondrial activity, which consisted of a stimulation of mitochondrial electron transport and cellular bioenergetic function at lower concentrations (30-100 nM) and an inhibitory effect at the higher concentration of 300 nM. Under oxidative stress conditions induced by glucose oxidase, an increase in oxidative protein modification and an enhancement in MitoSOX oxidation was noted, coupled with an inhibition of cellular bioenergetic function and a reduction in cell viability. AP39 pretreatment attenuated these responses. Glucose oxidase induced a preferential damage to the mitochondrial DNA; AP39 (100 nM) pretreatment protected against it. In conclusion, the current paper documents antioxidant and cytoprotective effects of AP39 under oxidative stress conditions, including a protection against oxidative mitochondrial DNA damage.
Abstract.
Author URL.
Tomasova L, Misak A, Kristek F, Perry A, Wood ME, Ondrias K, Whiteman M (2014). Effects of a Novel Triphenylphosphonium Derivatised Anethole Dithiolethione Hydrogen Sulfide (H2S) Donor, AP39, on Cardiac Ion Channels and on Haemodynamic Parameters in Normotensive and Hypertensive Rats in Vivo.
Author URL.
Whiteman M, Perry A, Wood ME (2014). H2S in inflammation: Time for resolution?.
Author URL.
Gero D, Szczesny B, Modis K, Yanagi K, Wood ME, Perry A, Szabo C, Whiteman M (2014). Mitochondira-targeted hydrogen sulfide donors AP39 and AP123 attenuate hyperglycaemia-induced oxidative stress and loss of bioenergetics in microvascular endothelial cells.
Author URL.
Gero D, Szczesny B, Perry A, Modis K, Wood ME, Szabo C, Whiteman M (2014). Novel Mitochondria-Targeted Hydrogen Sulfide (H2S) Donors AP39 and AP123 Attenuate Hyperglycaemia-Induced Oxidative Stress and Loss of Bioenergetics in Microvascular Endothelial Cells.
Author URL.
Ferguson D, Perry A, Wood ME, Winyard PG, Whiteman M (2014). Potentiation of Methyl Aminolevulinate (MAL)-Induced Photodynamic Therapy (PDT) Killing of Skin Cancer Cells by Mitochondria-Targeted Hydrogen Sulfide (H2S) Donors.
Author URL.
Le Trionnaire S, Perry A, Szczesny B, Szabo C, Winyard PG, Whatmore JL, Wood ME, Whiteman M (2014). The synthesis and functional evaluation of a mitochondria-targeted hydrogen sulfide donor, (10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5-yl)phenoxy)decyl) triphenylphosphonium bromide (AP39).
MedChemComm,
5(6), 728-736.
Abstract:
The synthesis and functional evaluation of a mitochondria-targeted hydrogen sulfide donor, (10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5-yl)phenoxy)decyl) triphenylphosphonium bromide (AP39)
Synthesis and bioavailability of the endogenous gasomediator hydrogen sulfide (H2S) is perturbed in many disease states, including those involving mitochondrial dysfunction. There is intense interest in developing pharmacological agents to generate H2S. We have synthesised a novel H2S donor molecule coupled to a mitochondria-targeting moiety (triphenylphosphonium; TPP+) and compared the effectiveness of the compound against a standard non-TPP+ containing H2S donor (GYY4137) in the inhibition of oxidative stress-induced endothelial cell death. Our study suggests mitochondria-targeted H2S donors are useful pharmacological tools to study the mitochondrial physiology of H2S in health and disease. © 2014 the Partner Organisations.
Abstract.
2013
Le Trionnaire S, Perry A, Whatmore JL, Wood ME, Whiteman M (2013). Mitochondria-targeted hydrogen sulfide donors: a novel twist to an old "tail"?.
Author URL.
Whiteman M, Perry A, Le Trionnaire S, Whatmore JL, Ahmed T, Fox B, Kerr P, Haigh R, Winyard PG, Wood ME, et al (2013). Modulation of inflammatory and vascular signalling by novel slow release and mitochondria-targeted H2S donors.
Author URL.
Whatmore JL, Wolanska KI, Perry A, Wood ME, Whiteman M (2013). Slow release hydrogen sulfide (H2S) donors prevent hyperglycaemia-induced glycocalyx loss in retinal mirovascular endothelial cells.
Author URL.
2012
Fox B, Perry A, Winyard P, Wood ME, Whiteman M (2012). Characterising the effect of novel slow-release H2S donors on pro-inflammatory enzyme activity in human cartilage cells.
Author URL.
Fox B, Holland T, Perry A, Wood ME, Whiteman M (2012). Characterising the effect of novel slow-release H2S donors on pro-inflammatory enzyme activity in human cartilage cells.
Author URL.
Whiteman ML, Wood ME, Perry A (2012). Compounds for use in the treatment of plants.
Abstract:
Compounds for use in the treatment of plants
The invention relates to use of a compound in a treatment of a plant to promote plant growth wherein the compound is a salt comprising an anion of formula (1): or a conjugate acid thereof, wherein: R1, R2, R3, R4 and R5 are each independently selected from H, halogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2- C10 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted C3-Ci0 cycloalkynyl, hydroxy, optionally substituted C1 -C10 alkoxy, amino, mono-(C1-C10 alkyl)amino and di-(C1-C10 alkyl)amino groups; and Y is a nitrogen containing heterocyclyl group having from 3 to 14 ring atoms, a nitrogen containing heteroaryl group having from 3 to 14 ring atoms, an optionally substituted mono-(C1-C10 alkyl)amino group, an optionally substituted di-(C1-C10 alkyl)amino group or an optionally substituted tri-(C1-C10 alkyl)amino group. The compounds can be used to prevent or reduce stomatal closure or to cause stomatal opening in a plant. The invention further provides compounds for use in a herbicidal treatment of a plant. New compounds and a method for their manufacture are also described.
Abstract.
Author URL.
Fox B, Holland T, Perry A, Winyard PG, Wood ME, Whiteman M (2012). Defining the Effect of Novel Slow-Release H2S Donors on Pro-Inflammatory Mediators and Enzymes in Human Joint Cells.
Author URL.
Yong QC, Cheong JL, Hua F, Deng LW, Khoo YM, Lee HS, Perry A, Wood M, Whiteman M, Bian JS, et al (2012). Erratum: Regulation of heart function by endogenous gaseous mediators-crosstalk between nitric oxide and hydrogen sulfide (Antioxidants and Redox Signaling (2011) 14 (2081-2091)). Antioxidants and Redox Signaling, 16(7).
Wolanska K, Perry A, Wood ME, Chibber R, Whatmore J, Whiteman M (2012). Hydrogen sulfide - a novel guardian of the endothelial glycocalyx?.
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Le Trionnaire S, Perry A, Whatmore JL, Winyard PG, Wood ME, Whiteman M (2012). Mitochondria-Targeted Slow Release Hydrogen Donors: a Novel Link to an Old 'tail'?.
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Le Trionnaire S, Whatmore J, Perry A, Wood ME, Matthew W (2012). Slow release H2S donors protect human microvascular endothelial cells from oxidative stress induced cell death: Markedly increased potency by mitochondria-targeting.
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Le Trionnaire S, Whatmore JL, Perry A, Wood ME, Whiteman M (2012). Slow release H2S donors protect human microvascular endothelial cells from oxidative stress induced cell death: Markedly increased potency by mitochondria-targetting.
Author URL.
2011
Le Trionnaire S, Whatmore JL, Perry A, Wood ME, Whiteman M (2011). Endogenous hydrogen sulfide (H2 S) and novel slow release H2S donors protect human endothelial cells from oxidative stress-induced cell death.
Author URL.
Le Trionnaire S, Whatmore J, Perry A, Wood ME, Whiteman M (2011). Endogenous hydrogen sulphide (H2S) and novel slow release H2S donors protect human microvascular endothelial cells from oxidative stress-induced cell death.
Author URL.
Yong Q-C, Cheong JL, Hua F, Deng L-W, Khoo YM, Lee H-S, Perry A, Wood M, Whiteman M, Bian J-S, et al (2011). Regulation of heart function by endogenous gaseous mediators-crosstalk between nitric oxide and hydrogen sulfide.
Antioxid Redox Signal,
14(11), 2081-2091.
Abstract:
Regulation of heart function by endogenous gaseous mediators-crosstalk between nitric oxide and hydrogen sulfide.
Both nitric oxide (NO) and hydrogen sulfide (H(2)S) are two important gaseous mediators regulating heart function. The present study examined the interaction between these two biological gases and its role in the heart. We found that l-arginine, a substrate of NO synthase, decreased the amplitudes of myocyte contraction and electrically induced calcium transients. Sodium hydrogen sulfide (an H(2)S donor), which alone had minor effect, reversed the negative inotropic effects of l-arginine. The effect of l-arginine + sodium hydrogen sulfide was abolished by three thiols (l-cysteine, N-acetyl-cysteine, and glutathione), suggesting that the effect of H(2)S + NO is thiol sensitive. The stimulatory effect on heart contractility was also induced by GYY4137, a slow-releasing H(2)S donor, when used together with sodium nitroprusside, an NO-releasing donor. More importantly, enzymatic generation of H(2)S from recombinant cystathionine-γ-lyase protein also interacted with endogenous NO generated from l-arginine to stimulate heart contraction. In summary, our data suggest that endogenous NO may interact with H(2)S to produce a new biological mediator that produces positive inotropic effect. The crosstalk between H(2)S and NO also suggests an intriguing potential for the endogenous formation of a thiol-sensitive molecule, which may be of physiological significance in the heart.
Abstract.
Author URL.
2010
Chopra M, Perry A, Hodgkinson A, Wood ME, Whiteman M (2010). Contrasting Effects of 'Fast' and 'Slow' Releasing H2S Donors on beta Cell Viability in the Diabetic Milieu.
Author URL.
Klein JEMN, Perry A, Pugh DS, Taylor RJK (2010). First C-H activation route to oxindoles using copper catalysis.
Org Lett,
12(15), 3446-3449.
Abstract:
First C-H activation route to oxindoles using copper catalysis.
The preparation of 3,3-disubstituted oxindoles by a formal C-H, Ar-H coupling of anilides is described. Highly efficient conditions have been identified using catalytic (5 mol %) Cu(OAc)(2).H(2)O with atmospheric oxygen as the reoxidant; no additional base is required, and the reaction can be run in toluene or mesitylene. Optimization studies are reported together with a scope and limitation investigation based on variation of the anilide precursors. The application of this methodology to prepare a key intermediate for the total synthesis of the anticancer, analgesic oxindole alkaloid Horsfiline is also described.
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Author URL.
Pugh DS, Klein JEMN, Perry A, Taylor RJK (2010). Preparation of 3-alkyl-oxindoles by copper(II)-mediated C-H, Ar-H coupling followed by decarboxyalkylation.
Synlett(6), 934-938.
Abstract:
Preparation of 3-alkyl-oxindoles by copper(II)-mediated C-H, Ar-H coupling followed by decarboxyalkylation
A novel route for the conversion of anilides into 3-alkyl-oxindoles is described in which a copper(II)-mediated cyclization process is followed by an acid-mediated decarboxyalkylation. Scope and limitation studies are reported together with a telescoped variant which incorporates in situ N-deprotection. © Georg Thieme Verlag Stuttgart - New York.
Abstract.
Lubkoll J, Millemaggi A, Perry A, Taylor RJK (2010). Tandem Horner-Wadsworth-Emmons/Heck procedures for the preparation of 3-alkenyl-oxindoles: the synthesis of Semaxanib and GW441756.
Tetrahedron,
66(33), 6606-6612.
Abstract:
Tandem Horner-Wadsworth-Emmons/Heck procedures for the preparation of 3-alkenyl-oxindoles: the synthesis of Semaxanib and GW441756
A tandem sequence involving Horner-Wadsworth-Emmons (HWE) olefination followed by a palladium-catalysed intramolecular Heck reaction has been developed to provide rapid access to 3-alkenyl-oxindoles from α-halo-anilides. This one-pot microwave accelerated process proceeds with catalytic palladium(II) acetate or tetrakis(triphenylphosphine)palladium, and has been used to prepare a range of adducts derived from aromatic, heteroaromatic and aliphatic aldehydes. The procedures can be used to prepare N-unprotected oxindoles directly and the applicability of the process has been established by carrying out one-pot syntheses of Semaxanib, an angiogenesis signalling inhibitor, and GW441756, an aza-oxindole Trk a inhibitor. © 2010 Elsevier Ltd.
Abstract.
2009
Nelson A, Bone H, Damiano M, Welham M, Bartlett S, Perry A, Cordier CJ, Warriner S, Leach SG, Morton D, et al (2009). Exploring biologically-relevant chemical space with macrocyclic ligands.
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY,
238 Author URL.
Bone HK, Damiano T, Bartlett S, Perry A, Letchford J, Ripoll YS, Nelson AS, Welham MJ (2009). Involvement of GSK-3 in Regulation of Murine Embryonic Stem Cell Self-Renewal Revealed by a Series of Bisindolylmaleimides.
Chemistry and Biology,
16(1), 15-27.
Abstract:
Involvement of GSK-3 in Regulation of Murine Embryonic Stem Cell Self-Renewal Revealed by a Series of Bisindolylmaleimides
The ability to propagate embryonic stem cells (ESCs) while maintaining their pluripotency is critical if their potential use in regenerative medicine is to be realized. The mechanisms controlling ESC self-renewal are under intense investigation, and glycogen synthase kinase 3 (GSK-3) has been implicated in regulating both self-renewal and differentiation. To clarify its role in ESCs we have used chemical genetics. We synthesized a series of bisindolylmaleimides, a subset of which inhibit GSK-3 in murine ESCs and robustly enhance self-renewal in the presence of leukemia inhibitory factor (LIF) and serum, but not in the absence of LIF. Importantly, these molecules appear selective for GSK-3 and do not perturb other signaling pathways regulating self-renewal. Our study clarifies the functional importance of GSK-3 in regulation of ESC self-renewal and provides tools for investigating its role further. © 2009 Elsevier Ltd. All rights reserved.
Abstract.
Perry A, Taylor RJK (2009). Oxindole synthesis by direct C-H, Ar-H coupling.
Chem Commun (Camb)(22), 3249-3251.
Abstract:
Oxindole synthesis by direct C-H, Ar-H coupling.
A novel copper(II)-mediated route for the conversion of anilides into 3,3-disubstituted-oxindoles is described which proceeds via a formal C-H, Ar-H coupling process.
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Author URL.
Millemaggi A, Perry A, Whitwood AC, Taylor RJK (2009). Telescoped enolate arylation/HWE procedure for the preparation of 3-alkenyl-oxindoles: the first synthesis of soulieotine.
European Journal of Organic Chemistry(18), 2947-2952.
Abstract:
Telescoped enolate arylation/HWE procedure for the preparation of 3-alkenyl-oxindoles: the first synthesis of soulieotine
A. telescoped sequence involving palladium-catalysed intramolecular enolate arylation followed by an in situ HWE olefination has been developed to provide rapid access to 3-alkenyl-oxindoles. This "one-pot" process, which is greatly accelerated by microwave irradiation, proceeds with low loadings of palladium (II) acetate (0.2-1.0 mol-%), and has been used to prepare a range of adducts derived from aromatic, heteroaromatic and aliphatic aldehydes as well as formaldehyde. In addition, further elaboration of the formaldehyde adducts are described. The applicability of the process has been established by carrying out the first synthesis of Soulieotine, a constituent of a traditional Chinese medicine. © Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009.
Abstract.
2008
McAllister GD, Perry A, Taylor RJK (2008). Diaziridines and diazirines. In (Ed) Comprehensive Heterocyclic Chemistry III, 539-557.
Edwards MG, Kenworthy MN, Kitson RRA, Perry A, Scott MS, Whitwood AC, Taylor RJK (2008). The preparation of α-alkylidene-γ-butyrolactones using a telescoped intramolecular Michael/Olefination (TIMO) sequence: Synthesis of (+)-paeonilactone B.
European Journal of Organic Chemistry(28), 4769-4783.
Abstract:
The preparation of α-alkylidene-γ-butyrolactones using a telescoped intramolecular Michael/Olefination (TIMO) sequence: Synthesis of (+)-paeonilactone B
A novel telescoped intramolecular Michael addition/proton transfer/HWE olefination sequence has been developed to provide rapid access to α-alkylidene-γ-butyrolactones. This methodology has been applied to prepare a range of tetrahydrobenzofuran-2,5-diones, and related systems, and also utilised in an extremely short synthesis of the natural product (+)-paeonilactone B in enantiomerically pure form. In addition, preliminary experiments are described that illustrate a palladium-catalysed variant proceeding by way of a π-allyl intermediate. © Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
Abstract.
2007
Hodgson R, Kennedy A, Nelson A, Perry A (2007). Synthesis of 3-sulfonyloxypyridines: Oxidative ring expansion of alpha-furylsulfonamides and N -> O sulfonyl transfer.
SYNLETT(7), 1043-1046.
Author URL.
2005
Kennedy A, Nelson A, Perry A (2005). A general, two-directional approach to aza-C-(1 → 1)-linked disaccharide mimetics.
Chemical Communications(12), 1646-1648.
Abstract:
A general, two-directional approach to aza-C-(1 → 1)-linked disaccharide mimetics
The Upjohn and Donohoe dihydroxylations were exploited in divergent syntheses of aza-C-(1 → 1)-linked disaccharides. © the Royal Society of Chemistry 2005.
Abstract.
Kennedy A, Nelson A, Perry A (2005). Methods for the synthesis of polyhydroxylated piperidines by diastereoselective dihydroxylation: Exploitation in the two-directional synthesis of aza-C-linked disaccharide derivatives.
Beilstein Journal of Organic Chemistry,
1Abstract:
Methods for the synthesis of polyhydroxylated piperidines by diastereoselective dihydroxylation: Exploitation in the two-directional synthesis of aza-C-linked disaccharide derivatives
Background: Many polyhydroxylated piperidines are inhibitors of the oligosaccharide processing enzymes, glycosidases and glycosyltransferases. Aza-C-linked disaccharide mimetics are compounds in which saturated polyhydroxylated nitrogen and oxygen heterocycles are linked by an all-carbon tether. The saturated oxygen heterocycle has the potential to mimic the departing sugar in a glycosidase-catalysed reaction and aza-C-linked disaccharide mimetics may, therefore, be more potent inhibitors of these enzymes. Results: the scope, limitations and diastereoselectivity of the dihydroxylation of stereoisomeric 2-butyl-1-(toluene-4-sulfonyl)-1,2,3,6- tetrahydro-pyridin-3-ols is discussed. In the absence of a 6-substituent on the piperidine ring, the Upjohn (cat. OsO4, NMO, acetone-water) and Donohoe (OsO4, TMEDA, CH2Cl2) conditions allow complementary diastereoselective functionalisation of the alkene of the (2R*,3R*) diastereoisomer. However, in the presence of a 6-substituent, the reaction is largely controlled by steric effects with both reagents. The most synthetically useful protocols were exploited in the two-directional synthesis of aza-C-linked disaccharide analogues. A two-directional oxidative ring expansion was used to prepare bis-enones such as (2R,6S,2′S)-6-methoxy-2-(6-methoxy-3-oxo-3,6-dihydro-2H-pyran-2-ylmethyl) -1-(toluene-4-sulfonyl)-1,6-dihydro-2H-pyridin-3-one from the corresponding difuran. Selective substitution of its N,O acetal was possible. The stereochemical outcome of a two-directional Luche reduction step was different in the two heterocyclic rings, and depended on the conformation of the ring. Finally, two-directional diastereoselective dihydroxylation yielded seven different aza-C-linked disaccharide analogues. Conclusion: a two-directional approach may be exploited in the synthesis of aza-C-linked disaccharide mimetics. Unlike previous approaches to similar molecules, neither of the heterocyclic rings is directly derived from a sugar, allowing mimetics with unusual configurations to be prepared. The work demonstrates that highly unsymmetrical molecules may be prepared using a two directional approach. The deprotected compounds may have potential as inhibitors of oligosaccharide- processing enzymes and as tools in chemical genetic investigations. © 2005 Kennedy et al; licensee Beilstein-Institut.
Abstract.
2004
Kennedy A, Nelson A, Perry A (2004). Highly diastereoselective addition of ketone enolates to N-sulfinyl imines: Asymmetric synthesis of syn- and anti-1,3-amino alcohol derivatives.
Synlett(6), 967-970.
Abstract:
Highly diastereoselective addition of ketone enolates to N-sulfinyl imines: Asymmetric synthesis of syn- and anti-1,3-amino alcohol derivatives
Lithium enolates derived from ketones may be added to N-sulfinyl imines with high diastereoselectivity. Diastereoselective reduction gave either the syn- or anti-1,3-amino alcohol derivative.
Abstract.
2002
Armstrong SK, Cross RJ, Farrugia LJ, Nichols DA, Perry A (2002). Semi-rigid bis-phosphane ligands for metallamacrocycle formation.
European Journal of Inorganic Chemistry(1), 141-151.
Abstract:
Semi-rigid bis-phosphane ligands for metallamacrocycle formation
Efficient syntheses are described for the new bridging bis- phosphanes DPPN (4) and DPEN (5) built around the restricted rigidity of a 2,7-dialkoxynaphthalene backbone. These show marked preference for bridging pairs of metal atoms (Pt11, Mo0) to form metallamacrocycles or oligomers. Single-crystal X-ray structure determinations of four dimeric complexes with PtII and Mo0 are reported. The dimeric platinum complexes can be obtained as the kinetically favoured trans,trans products, which isomerise to the cis,cis forms in the presence of free ligand. cis,cis-[Pt2Cl4(DPEN)2] (12) shows marked hydroformylation catalytic activity.
Abstract.