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Article ; Online: Leveraging Pyrazolium Ylide Reactivity to Access Indolizine and 1,2-Dihydropyrimidine Derivatives.

Tran, Ricky / Brownsey, Duncan K / O'Sullivan, Leonie / Brandow, Connor M J / Chang, Emily S / Zhou, Wen / Patel, Ketul V / Gorobets, Evgueni / Derksen, Darren J

Chemistry (Weinheim an der Bergstrasse, Germany)

2024 , Page(s) e202400421

Abstract: N-Heterocyclic ylides are important synthetic precursors to rapidly build molecular complexity. Pyrazolium ylides have largely been unexplored, and we demonstrate their diverse utility in this report. We show that these readily accessible building blocks ...

Abstract	N-Heterocyclic ylides are important synthetic precursors to rapidly build molecular complexity. Pyrazolium ylides have largely been unexplored, and we demonstrate their diverse utility in this report. We show that these readily accessible building blocks can be used to construct different heterocyclic skeletons by varying the coupling partner. Indolizines can be formed via an N-deletion type mechanism when reacting pyrazolium salts with electron deficient alkynes. 1,2-Dihydropyrimidines can be formed via a rearrangement mechanism when reacting pyrazolium ylides with isocyanates. These reactions enable access to valuable heteroarenes without the need for transition metal catalysis, high temperatures, or strong bases.
Language	English
Publishing date	2024-03-13
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1478547-X
ISSN	1521-3765 ; 0947-6539
ISSN (online)	1521-3765
ISSN	0947-6539
DOI	10.1002/chem.202400421
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Article ; Online: A vinylogous Norrish reaction as a strategy for light-mediated ring expansion.

Gorobets, Evgueni / Papatzimas, James W / Dourado, Jorge / Yousefalizadeh, Goonay / Lee, JinGyu / Brownsey, Duncan K / Stamplecoskie, Kevin / Davis, Rebecca / Derksen, Darren J

Chemical communications (Cambridge, England)

2022 Volume 58, Issue 17, Page(s) 2910–2913

Abstract: The reactions of bicyclic divinyl ketones display wavelength-dependent changes in product formation. UV irradiation results in the formation of competitive [6,3,5] and [7,3,5] tricyclic unsaturated ketones that subsequently undergo ring expansion and ... ...

Abstract	The reactions of bicyclic divinyl ketones display wavelength-dependent changes in product formation. UV irradiation results in the formation of competitive [6,3,5] and [7,3,5] tricyclic unsaturated ketones that subsequently undergo ring expansion and reaction with a range of nucleophiles. DFT calculations and transient absorption experiments were completed that are consistent with a vinylogous Type II Norrish pathway.
Language	English
Publishing date	2022-02-24
Publishing country	England
Document type	Journal Article
ZDB-ID	1472881-3
ISSN	1364-548X ; 1359-7345 ; 0009-241X
ISSN (online)	1364-548X
ISSN	1359-7345 ; 0009-241X
DOI	10.1039/d2cc00513a
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Article ; Online: Identification of ligand linkage vectors for the development of p300/CBP degraders.

Brownsey, Duncan K / Rowley, Ben C / Gorobets, Evgueni / Mihara, Koichiro / Maity, Ranjan / Papatzimas, James W / Gelfand, Benjamin S / Hollenberg, Morley D / Bahlis, Nizar J / Derksen, Darren J

RSC medicinal chemistry

2022 Volume 13, Issue 6, Page(s) 726–730

Abstract: To develop new degrader molecules from an existing protein ligand a linkage vector must be identified and then joined with a suitable E3 ligase without disrupting binding to the respective targets. This is typically achieved through empirically ... ...

Abstract	To develop new degrader molecules from an existing protein ligand a linkage vector must be identified and then joined with a suitable E3 ligase without disrupting binding to the respective targets. This is typically achieved through empirically evaluating the degradation efficacy of a series of synthetic degraders. Our strategy for determining optimal linkage sites utilises biotinylated protein ligands, linked
Language	English
Publishing date	2022-04-14
Publishing country	England
Document type	Journal Article
ISSN	2632-8682
ISSN (online)	2632-8682
DOI	10.1039/d1md00070e
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Article ; Online: Regulation of mitochondrial aconitase by phosphorylation in diabetic rat heart.

Lin, G / Brownsey, R W / MacLeod, K M

Cellular and molecular life sciences : CMLS

2009 Volume 66, Issue 5, Page(s) 919–932

Abstract: Mitochondrial dysfunction and protein kinase C (PKC) activation are consistently found in diabetic cardiomyopathy but their relationship remains unclear. This study identified mitochondrial aconitase as a downstream target of PKC activation using ... ...

Abstract	Mitochondrial dysfunction and protein kinase C (PKC) activation are consistently found in diabetic cardiomyopathy but their relationship remains unclear. This study identified mitochondrial aconitase as a downstream target of PKC activation using immunoblotting and mass spectrometry, and then characterized phosphorylation-induced changes in its activity in hearts from type 1 diabetic rats. PKCbeta(2) co-immunoprecipitated with phosphorylated aconitase from mitochondria isolated from diabetic hearts. Augmented phosphorylation of mitochondrial aconitase in diabetic hearts was found to be associated with an increase in its reverse activity (isocitrate to aconitate), while the rate of the forward activity was unchanged. Similar results were obtained on phosphorylation of mitochondrial aconitase by PKCbeta(2) in vitro. These results demonstrate the regulation of mitochondrial aconitase activity by PKC-dependent phosphorylation. This may influence the activity of the tricarboxylic acid cycle, and contribute to impaired mitochondrial function and energy metabolism in diabetic hearts.
MeSH term(s)	ATP Citrate (pro-S)-Lyase/metabolism ; Aconitate Hydratase/chemistry ; Aconitate Hydratase/genetics ; Aconitate Hydratase/metabolism ; Amino Acid Sequence ; Animals ; Citric Acid Cycle/physiology ; Diabetes Mellitus, Experimental/metabolism ; Enzyme Activation ; Humans ; Immunohistochemistry ; Isoenzymes/metabolism ; Mitochondria/enzymology ; Mitochondria/ultrastructure ; Models, Molecular ; Molecular Sequence Data ; Myocardium/cytology ; Myocardium/enzymology ; Phosphorylation ; Protein Kinase C/metabolism ; Protein Structure, Tertiary ; Rats ; Rats, Wistar ; Signal Transduction/physiology
Chemical Substances	Isoenzymes ; ATP Citrate (pro-S)-Lyase (EC 2.3.3.8) ; Protein Kinase C (EC 2.7.11.13) ; Aconitate Hydratase (EC 4.2.1.3)
Language	English
Publishing date	2009-03
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-009-8696-3
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Article ; Online: Complex regulation of PKCβ2 and PDK-1/AKT by ROCK2 in diabetic heart.

Guorong Lin / Roger W Brownsey / Kathleen M Macleod

PLoS ONE, Vol 9, Iss 1, p e

2014 Volume 86520

Abstract: The RhoA/ROCK pathway contributes to diabetic cardiomyopathy in part by promoting the sustained activation of PKCβ2 but the details of their interaction are unclear. The purpose of this study was to investigate if over-activation of ROCK in the diabetic ... ...

Abstract	The RhoA/ROCK pathway contributes to diabetic cardiomyopathy in part by promoting the sustained activation of PKCβ2 but the details of their interaction are unclear. The purpose of this study was to investigate if over-activation of ROCK in the diabetic heart leads to direct phosphorylation and activation of PKCβ2, and to determine if their interaction affects PDK-1/Akt signaling.Regulation by ROCK of PKCβ2 and related kinases was investigated by Western blotting and co-immunoprecipitation in whole hearts and isolated cardiomyocytes from 12 to 14-week diabetic rats. Direct ROCK2 phosphorylation of PKCβ2 was examined in vitro. siRNA silencing was used to confirm role of ROCK2 in PKCβ2 phosphorylation in vascular smooth muscle cells cultured in high glucose. Furthermore, the effect of ROCK inhibition on GLUT4 translocation was determined in isolated cardiomyocytes by confocal microscopy.Expression of ROCK2 and expression and phosphorylation of PKCβ2 were increased in diabetic hearts. A physical interaction between the two kinases was demonstrated by reciprocal immunoprecipitation, while ROCK2 directly phosphorylated PKCβ2 at T641 in vitro. ROCK2 siRNA in vascular smooth muscle cells or inhibition of ROCK in diabetic hearts reduced PKCβ2 T641 phosphorylation, and this was associated with attenuation of PKCβ2 activity. PKCβ2 also formed a complex with PDK-1 and its target AKT, and ROCK inhibition resulted in upregulation of the phosphorylation of PDK-1 and AKT, and increased translocation of glucose transporter 4 (GLUT4) to the plasma membrane in diabetic hearts.This study demonstrates that over-activation of ROCK2 contributes to diabetic cardiomyopathy by multiple mechanisms, including direct phosphorylation and activation of PKCβ2 and interference with the PDK-1-mediated phosphorylation and activation of AKT and translocation of GLUT4. This suggests that ROCK2 is a critical node in the development of diabetic cardiomyopathy and may be an effective target to improve cardiac function in diabetes.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article: A General Strategy for the Preparation of Thalidomide-Conjugate Linkers

Papatzimas, James W. / Gorobets, Evgueni / Brownsey, Duncan K. / Maity, Ranjan / Bahlis, Nizar J. / Derksen, Darren J.

Synlett

2017 Volume 28, Issue 20, Page(s) 2881–2885

Abstract: The synthesis of small-molecule linkers for installation of thalidomide-based conjugates is described. Linker properties have been recognized as vital to conjugate success in drug discovery and delivery systems. These small-molecule tethers act as ... ...

Abstract	The synthesis of small-molecule linkers for installation of thalidomide-based conjugates is described. Linker properties have been recognized as vital to conjugate success in drug discovery and delivery systems. These small-molecule tethers act as linkages between molecules, can also aid in cell permeability, and act as solubilizing agents. This work shows our progress in synthesizing conjugates with a variety of linker characteristics. The adaptability and manipulation of these and other linkers holds potential in improving synthetic control of chemical connectivities toward therapeutic development.
Keywords	PROTAC ; thalidomide ; conjugates ; linker ; pentafluorophenyl ester
Language	English
Publishing date	2017-08-23
Publisher	© Georg Thieme Verlag
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	2042012-2
ISSN	1437-2096 ; 0936-5214
ISSN (online)	1437-2096
ISSN	0936-5214
DOI	10.1055/s-0036-1588539
Database	Thieme publisher's database

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Article: Inhibition of cyclic AMP dependent protein kinase by vanadyl sulfate.

Jelveh, Kioumars A / Zhande, Rachel / Brownsey, Roger W

Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry

2006 Volume 11, Issue 3, Page(s) 379–388

Abstract: Vanadium salts influence the activities of a number of mammalian enzymes in vitro but the mechanisms by which low concentrations of vanadium ameliorate the effects of diabetes in vivo remain poorly understood. The hypothesis that vanadium compounds act ... ...

Abstract	Vanadium salts influence the activities of a number of mammalian enzymes in vitro but the mechanisms by which low concentrations of vanadium ameliorate the effects of diabetes in vivo remain poorly understood. The hypothesis that vanadium compounds act by inhibiting protein tyrosine phosphatases has attracted most support. The studies described here further evaluate the possibility that vanadyl sulfate trihydrate (VS) can also inhibit 3',5'-cyclic adenosine monophosphate (cAMP) dependent protein kinase (PKA). Using conventional assay conditions, VS inhibited PKA only at high concentrations (IC50>400 microM); however, PKA inhibition was seen at dramatically lower concentrations of VS (IC50<10 microM) when sequestration of vanadyl ions was minimized. Vanadyl appears to be the effective PKA inhibitor because sodium orthovanadate did not inhibit PKA and inhibition by vanadyl was abolished by potential chelators such as ethylenediaminetetraacetic acid or glycyl peptides. PKA inhibition by vanadyl appears to be mixed rather than strictly competitive or uncompetitive and may replicate the inhibitory effects of high concentrations of Mg2+. The effect of vanadyl on PKA provides a possible explanation for the effects of vanadium salts on fat tissue lipolysis and perhaps on other aspects of energy metabolism that are controlled by cAMP-dependent mechanisms. Considering the high degree of conservation of the active sites of protein kinases, vanadyl may also influence other members of this large protein family.
MeSH term(s)	Animals ; Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors ; Electron Spin Resonance Spectroscopy ; Magnesium/metabolism ; Male ; Oligopeptides/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Rats ; Rats, Wistar ; Vanadium Compounds/pharmacology
Chemical Substances	Oligopeptides ; Protein Kinase Inhibitors ; Vanadium Compounds ; kemptide (65189-71-1) ; vanadyl sulfate (6DU9Y533FA) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Magnesium (I38ZP9992A)
Language	English
Publishing date	2006-04
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1464026-0
ISSN	1432-1327 ; 0949-8257
ISSN (online)	1432-1327
ISSN	0949-8257
DOI	10.1007/s00775-006-0087-8
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Article: Cell volume and the metabolic actions of insulin.

Zhande, R / Brownsey, R W

Biochemistry and cell biology = Biochimie et biologie cellulaire

1996 Volume 74, Issue 4, Page(s) 513–522

Abstract: Insulin increases the volume of isolated hepatocytes and cells in perfused livers, but effects of the hormone on the volume of fat or muscle cells have not been demonstrated. Exogenous amino acids may stimulate swelling of liver cells and induce insulin- ... ...

Abstract	Insulin increases the volume of isolated hepatocytes and cells in perfused livers, but effects of the hormone on the volume of fat or muscle cells have not been demonstrated. Exogenous amino acids may stimulate swelling of liver cells and induce insulin-like effects on hepatic protein metabolism; however, swelling of liver cells can be induced by some treatment that do not induce insulin-like metabolic responses. Exogenous amino acids also influence protein metabolism of fat and muscle cells, but no relationship with cell volume has been established and no corresponding effects on metabolism of carbohydrates or lipids have been observed. Three families of mitogen-activated protein kinases are activated after changes in extracellular osmolarity but they appear to play little or no role in the metabolic actions of insulin. Direct evidence against a metabolic role for the extracellular signal-regulated kinases ERK-1 and ERK-2 is discussed. The c-Jun N-terminal kinases (also called stress-activated protein kinases) and the mammalian homologs of the yeast Hog protein kinase are strongly activated by environmental stresses associated with catabolic metabolism. We conclude that cell volume and protein metabolism may be correlated in liver but there is no compelling evidence that the effects of insulin on metabolism of liver, fat, or muscle cells can be accounted for by changes in cell volume. The effects of insulin on cell volume may represent a discrete aspect of the complete physiological response rather than an obligatory intermediate step in metabolic signalling.
MeSH term(s)	Adipocytes/cytology ; Adipocytes/metabolism ; Animals ; Calcium-Calmodulin-Dependent Protein Kinases/metabolism ; Carbohydrate Metabolism ; Cell Size ; Insulin/pharmacology ; Ion Transport ; Kinetics ; Lipid Metabolism ; Liver/cytology ; Liver/metabolism ; Muscles/cytology ; Muscles/metabolism ; Osmolar Concentration ; Proteins/metabolism ; Signal Transduction/drug effects
Chemical Substances	Insulin ; Proteins ; Calcium-Calmodulin-Dependent Protein Kinases (EC 2.7.11.17)
Language	English
Publishing date	1996
Publishing country	Canada
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	54104-7
ISSN	0829-8211
ISSN	0829-8211
DOI	10.1139/o96-055
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Article: Evidence for selective effects of vanadium on adipose cell metabolism involving actions on cAMP-dependent protein kinase.

Brownsey, R W / Dong, G W

Molecular and cellular biochemistry

1995 Volume 153, Issue 1-2, Page(s) 131–137

Abstract: The insulin-like effects of vanadium in vivo are likely to be achieved at micromolar concentrations. Demonstrated effects of vanadium on adipose tissue of streptozotocin-diabetic rats include inhibition of basal and stimulated rates of lipolysis and ... ...

Abstract	The insulin-like effects of vanadium in vivo are likely to be achieved at micromolar concentrations. Demonstrated effects of vanadium on adipose tissue of streptozotocin-diabetic rats include inhibition of basal and stimulated rates of lipolysis and effects on fat cell protein phosphorylation. The studies described below examined the effects of vanadium (to a maximum concentration of 0.5 mM) on adipose cells or tissue in vitro. Vanadium, added as a vanadyl-albumin complex or as sodium orthovanadate, produced a marked (greater than 50%) inhibition of isoproterenol-stimulated lipolysis. Inhibition of lipolysis equivalent to that seen with insulin, was achieved with approximately 100 microM vanadium. In contrast, no insulin-like stimulation of de novo fatty acid biosynthesis was observed with vanadium below 0.5 mM. Surprisingly, the antilipolytic effects of vanadium persisted in the presence of cilostamide, an inhibitor of the insulin-sensitive isoform of cyclic nucleotide phosphodiesterase. Studies with purified preparations of the catalytic subunit of cyclic AMP-dependent protein kinase revealed dose-dependent inhibition with vanadyl-glutathione (to a maximum of approximately 40% inhibition). Equivalent inhibition of cyclic AMP-dependent phosphorylation of Kemptide (approximately 50%) was observed upon incubation of freshly-prepared fat-pad supernatant fractions with vanadyl-glutathione. These results suggest that effects of low concentrations of vanadium may be mediated, at least in part, by actions on the catalytic subunit of cyclic AMP-dependent protein kinase.
MeSH term(s)	Adipocytes/metabolism ; Animals ; Cells, Cultured ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Lipolysis/drug effects ; Male ; Rats ; Rats, Wistar ; Vanadium Compounds/pharmacology
Chemical Substances	Vanadium Compounds ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11)
Language	English
Publishing date	1995-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	184833-1
ISSN	1573-4919 ; 0300-8177
ISSN (online)	1573-4919
ISSN	0300-8177
DOI	10.1007/bf01075928
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Article: Hormonal regulation of acetyl-CoA carboxylase in epididymal adipose tissue.

Brownsey, R W

Biochemical Society transactions

1981 Volume 9, Issue 6, Page(s) 515–520

MeSH term(s)	Acetyl-CoA Carboxylase/isolation & purification ; Acetyl-CoA Carboxylase/metabolism ; Adipose Tissue/drug effects ; Adipose Tissue/enzymology ; Animals ; Chickens ; Epinephrine/pharmacology ; Insulin/pharmacology ; Ligases/metabolism ; Male ; Membrane Proteins/metabolism ; Protein Kinases/metabolism ; Rats
Chemical Substances	Insulin ; Membrane Proteins ; Protein Kinases (EC 2.7.-) ; Ligases (EC 6.-) ; Acetyl-CoA Carboxylase (EC 6.4.1.2) ; Epinephrine (YKH834O4BH)
Language	English
Publishing date	1981-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/bst0090515
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