Barry V L Potter

University of Bath, Bath, England, United Kingdom

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Publications (454)1655.88 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: A SAR translation strategy adopted for the discovery of tetrahydroisoquinolinone (THIQ)-based steroidomimetic microtubule disruptors has been extended to dihydroisoquinolinone (DHIQ)-based compounds. A steroid A,B-ring-mimicking DHIQ core was connected to methoxyaryl D-ring mimics through methylene, carbonyl, and sulfonyl linkers, and the resulting compounds were evaluated against two cancer cell lines. The carbonyl-linked DHIQs in particular exhibit significant in vitro antiproliferative activities (e.g., 6-hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-3,4-dihydroisoquinolin-1(2H)-one (16 g): GI50 51 nM in DU-145 cells). The broad anticancer activity of DHIQ 16 g was confirmed in the NCI 60-cell line assay giving a mean activity of 33 nM. Furthermore, 6-hydroxy-2-(3,5-dimethoxybenzoyl)-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (16 f) and 16 g and their sulfamate derivatives 17 f and 17 g (2-(3,5-dimethoxybenzoyl)-7-methoxy-6-sulfamoyloxy-3,4-dihydroisoquinolin-1(2H)-one and 7-methoxy-2-(3,4,5-trimethoxybenzoyl)-6-sulfamoyloxy-3,4-dihydroisoquinolin-1(2H)-one, respectively) show excellent activity against the polymerization of tubulin, close to that of the clinical combretastatin A-4, and bind competitively at the colchicine binding site of tubulin. Compounds 16 f and 17 f were also shown to demonstrate in vitro anti-angiogenic activity. Additionally, X-ray and computational analyses of 17 f reveal that electrostatic repulsion between the two adjacent carbonyl groups, through conformational biasing, dictates the adoption of a “steroid-like” conformation that may partially explain the excellent in vitro activities.
    ChemMedChem 03/2014; · 2.84 Impact Factor
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    ABSTRACT: The pattern recognition receptor RIG-I is critical for Type-I interferon production. However, the global regulation of RIG-I signaling is only partially understood. Using a human genome-wide RNAi-screen, we identified 226 novel regulatory proteins of RIG-I mediated interferon-β production. Furthermore, the screen identified a metabolic pathway that synthesizes the inositol pyrophosphate 1-IP7 as a previously unrecognized positive regulator of interferon production. Detailed genetic and biochemical experiments demonstrated that the kinase activities of IPPK, PPIP5K1 and PPIP5K2 (which convert IP5 to1-IP7) were critical for both interferon induction, and the control of cellular infection by Sendai and influenza A viruses. Conversely, ectopically expressed inositol pyrophosphate-hydrolases DIPPs attenuated interferon transcription. Mechanistic experiments in intact cells revealed that the expression of IPPK, PPIP5K1 and PPIP5K2 was needed for the phosphorylation and activation of IRF3, a transcription factor for interferon. The addition of purified individual inositol pyrophosphates to a cell free reconstituted RIG-I signaling assay further identified 1-IP7 as an essential component required for IRF3 activation. The inositol pyrophosphate may act by β-phosphoryl transfer, since its action was not recapitulated by a synthetic phosphonoacetate analogue of 1-IP7. This study thus identified several novel regulators of RIG-I, and a new role for inositol pyrophosphates in augmenting innate immune responses to viral infection that may have therapeutic applications.
    PLoS Pathogens 02/2014; 10(2):e1003981. · 8.14 Impact Factor
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    ABSTRACT: Analogues of the potent Ca(2+) releasing second messenger cyclic ADP-ribose (cADPR) with a 1,2,3-triazole pyrophosphate bioisostere were synthesised by click-mediated macrocyclisation. The ability to activate Ca(2+) release was surprisingly retained, and hydrolysis of cADPR by CD38 could also be inhibited, illustrating the potential of this approach to design drug-like signalling pathway modulators.
    Chemical Communications 01/2014; · 6.38 Impact Factor
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    ABSTRACT: The syntheses and antiproliferative activities of novel substituted tetrahydroisoquinoline derivatives and their sulfamates are discussed. Biasing of conformational populations through substitution on the tetrahydroisoquinoline core at C1 and C3 has a profound effect on the antiproliferative activity against various cancer cell lines. The C3 methyl-substituted sulfamate (±)-7-methoxy-2-(3-methoxybenzyl)-3-methyl-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (6 b), for example, was found to be ∼10-fold more potent than the corresponding non-methylated compound 7-methoxy-2-(3-methoxybenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (4 b) against DU-145 prostate cancer cells (GI50 values: 220 nM and 2.1 μM, respectively). Such compounds were also found to be active against a drug-resistant MCF breast cancer cell line. The position and nature of substitution of the N-benzyl group in the C3-substituted series was found to have a significant effect on activity. Whereas C1 methylation has little effect on activity, introduction of C1 phenyl and C3-gem-dimethyl substituents greatly decreases antiproliferative activity. The ability of these compounds to inhibit microtubule polymerisation and to bind tubulin in a competitive manner versus colchicine confirms the mechanism of action. The therapeutic potential of a representative compound was confirmed in an in vivo multiple myeloma xenograft study.
    ChemMedChem 01/2014; · 2.84 Impact Factor
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    ABSTRACT: When applied extracellularly, myo-inositol hexakisphosphate (InsP6 ) and myo-inositol pentakisphosphate (InsP5 ) can inhibit the growth and proliferation of tumour cells. There is debate about whether these effects result from interactions of InsP6 and InsP5 with intracellular or extracellular targets. We synthesised FAM-InsP5 , a fluorescent conjugate of InsP5 that allows direct visualisation of its interaction with cells. FAM-InsP5 was internalised by H1229 tumour cells, a finding that supports earlier reports that externally applied inositol phosphates can-perhaps surprisingly-enter into cells. Close examination of the process of FAM-InsP5 uptake suggests a mechanism of non-receptor-mediated endocytosis, which is blocked at 4 °C and probably involves interaction of the ligand with the glycocalyx. However, our results are difficult to reconcile with antiproliferative mechanisms that require direct interactions of externally applied InsP5 or InsP6 with cytosolic proteins, because internalised FAM-InsP5 appears in lysosomes and apparently does not enter the cytoplasm. Studies using FAM-InsP5 are less difficult and time-consuming than experiments using InsP5 or InsP6 , a factor that allowed us to analyse cellular uptake across a range of human cell types, identifying strong cell-specific differences.
    ChemBioChem 12/2013; · 3.74 Impact Factor
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    ABSTRACT: Adenosine 5'-diphosphoribose (ADPR) activates TRPM2, a Ca2+, Na+ and K+ permeable cation channel. Activation is induced by ADPR binding to the cytosolic C-terminal NudT9-homology domain. To generate the first structure-activity relationship, systematically-modified ADPR analogues were designed, synthesized and evaluated as antagonists using patch-clamp experiments in HEK293 cells over-expressing human TRPM2. Compounds with a purine C8 substituent show antagonist activity and an 8-phenyl substitution [8-Ph-ADPR, 5] is very effective. Modification of the terminal ribose results in a weak antagonist, whereas its removal abolishes activity. An antagonist based upon a hybrid structure, 8-phenyl-2-deoxy-ADPR (86, IC50 = 3 micro M), is more potent than 8-Ph-ADPR (5). Initial bioisosteric replacement of the pyrophosphate linkage abolishes activity, but replacement of the pyrophosphate and the terminal ribose by a sulfamate-based group leads to a weak antagonist, a lead to more drug-like analogues. 8-Ph-ADPR (5) inhibits Ca2+ signaling and chemotaxis in human neutrophils illustrating the potential for pharmacological intervention at TRPM2.
    Journal of Medicinal Chemistry 12/2013; · 5.61 Impact Factor
  • Mark P Thomas, Barry V L Potter
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    ABSTRACT: Diphospho-myo-inositol polyphosphates have many roles to play including roles in apoptosis, vesicle trafficking, the response of cells to stress, the regulation of telomere length and DNA damage repair, and inhibition of the cyclin-dependent kinase Pho85 system that monitors phosphate levels. This review focuses on the three classes of enzymes involved in the metabolism of these compounds - inositol hexakisphosphate kinases (IP6K), inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinases (PPIP5K), and diphosphoinositol polyphosphate phosphohydrolases (DIPP). However, these enzymes have roles beyond being mere catalysts, and their interactions with other proteins have cellular consequences. Through their interactions the three inositol hexakisphosphate kinases have roles in exocytosis, diabetes, the response to infection, and apoptosis. The two inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinases influence the cellular response to phosphatidylinositol (3,4,5)-trisphosphate and the migration of pleckstrin homology domain-containing proteins to the plasma membrane. The five diphosphoinositol polyphosphate phosphohydrolases interact with ribosomal proteins and transcription factors, and proteins involved in membrane trafficking, exocytosis, ubiquitination and the proteasomal degradation of target proteins. Possible directions for future research to further elucidate the roles of these enzymes are highlighted. This article is protected by copyright. All rights reserved.
    FEBS Journal 10/2013; · 4.25 Impact Factor
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    ABSTRACT: A structure-activity relationship (SAR) translation strategy was used for the discovery of tetrahydroisoquinoline (THIQ)-based steroidomimetic and chimeric microtubule disruptors based upon a steroidal starting point. A steroid A,B-ring-mimicking THIQ core was connected to methoxyaryl D-ring ring mimics through methylene, carbonyl and sulfonyl linkers to afford a number of steroidomimetic hits (e.g., 7-methoxy-2-(3- methoxybenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline (20 c) GI50 =2.1 μM). Optimisation and control experiments demonstrate the complementary SAR of this series and the steroid derivatives that inspired its design. Linkage of the THIQ-based A,B-mimic with the trimethoxyaryl motif prevalent in colchicine site binding microtubule disruptors delivered a series of chimeric molecules whose activity (GI50 =40 nM) surpasses that of the parent steroid derivatives. Validation of this strategy was obtained from the excellent oral activity of 7-methoxy-6-sulfamoyloxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline (20 z) relative to a benchmark steroidal bis- sulfamate in an in vivo model of multiple myeloma.
    ChemMedChem 10/2013; · 2.84 Impact Factor
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    ABSTRACT: Oh, what a difference an S makes: A thioribose analogue (cADPtR, see scheme) of cyclic ADP-ribose (cADPR) was synthesized that is stable and has structural and electrostatic features similar to those of cADPR. cADPtR is the first stable equivalent of cADPR that is as active as cADPR in various cellular systems, making it useful for investigating Ca(2+) ion-release signaling pathways.
    Angewandte Chemie International Edition 05/2013; · 13.73 Impact Factor
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    ABSTRACT: Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+ releasing second messenger known to date. Here we report a new role for NAADP in arrhythmogenic Ca2+ release in cardiac myocytes evoked by β-adrenergic stimulation. Infusion of NAADP into intact cardiac myocytes induced global Ca2+ signals sensitive to inhibitors of both acidic Ca2+ stores and ryanodine receptors and to NAADP antagonist BZ194. Furthermore, in electrically paced cardiac myocytes BZ194 blocked spontaneous diastolic Ca2+ transients caused by high concentrations of the β-adrenergic agonist isoproterenol. Ca2+ transients were recorded both as increases of the free cytosolic Ca2+ concentration and as decreases of the sarcoplasmic luminal Ca2+ concentration. Importantly, NAADP antagonist BZ194 largely ameliorated isoproterenol-induced arrhythmias in awake mice. We provide strong evidence that NAADP-mediated modulation of couplon activity plays a role for triggering (i) spontaneous diastolic Ca2+ transients in isolated cardiac myocytes and (ii) arrhythmias in the intact animal. Thus, NAADP signalling appears an attractive novel target for antiarrhythmic therapy.
    Journal of Biological Chemistry 04/2013; · 4.65 Impact Factor
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    ABSTRACT: 4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate and its ortho-halogenated (F, Cl, Br) derivatives are first-generation dual aromatase and sulfatase inhibitors (DASIs). Structure-activity relationship studies were performed on these compounds, and various modifications were made to their structures involving relocation of the halogen atom, introduction of more halogen atoms, replacement of the halogen with another group, replacement of the methylene linker with a difluoromethylene linker, replacement of the para-cyanophenyl ring with other ring structures, and replacement of the triazolyl group with an imidazolyl group. The most potent in vitro DASI discovered is an imidazole derivative with IC50 values against aromatase and steroid sulfatase in a JEG-3 cell preparation of 0.2 and 2.5 nM, respectively. The parent phenol of this compound inhibits aromatase with an IC50 value of 0.028 nM in the same assay.
    ChemMedChem 03/2013; · 2.84 Impact Factor
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    ABSTRACT: Acid hydrolysis of myo-inositol 1,3,5-orthoesters, apart from orthoformates, exclusively affords the corresponding 2-O-acyl myo-inositol products via a 1,2-bridged five-membered ring dioxolanylium ion intermediate observed by NMR spectroscopy. These C-2-substituted inositol derivatives provide valuable precursors for rapid and highly efficient routes to 2-O-acyl inositol 1,3,4,5,6-pentakisphosphates and myo-inositol 1,3,4,5,6-pentakisphosphate with biologically interesting and anticancer properties. Deuterium incorporation into the α-methylene group of such alkyl ester products (2-O-C(O)CD2R), when the analogous alkyl orthoester is treated with deuterated acid, is established utilizing the novel orthoester myo-inositol 1,3,5-orthobutyrate as an example. Such deuterated ester products provide intermediates for deuterium-labeled synthetic analogues. Investigation into this selective formation of 2-O-ester products and the deuterium incorporation is presented with proposed mechanisms from NMR experiments.
    The Journal of Organic Chemistry 03/2013; · 4.56 Impact Factor
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    Mark P Thomas, Barry V L Potter
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    ABSTRACT: Many enzymes catalyse reactions that have an estrogen as a substrate and/or a product. The reactions catalysed include aromatisation, oxidation, reduction, sulfonation, desulfonation, hydroxylation and methoxylation. The enzymes that catalyse these reactions must all recognize and bind estrogen but, despite this, they have diverse structures. This review looks at each of these enzymes in turn, describing the structure and discussing the mechanism of the catalysed reaction. Since estrogen has a role in many disease states inhibition of the enzymes of estrogen metabolism may have an impact on the state or progression of the disease and inhibitors of these enzymes are briefly discussed.
    The Journal of steroid biochemistry and molecular biology 01/2013; · 2.66 Impact Factor
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    ABSTRACT: Inositol 1,4,5-trisphosphate receptors (IP3R) and ryanodine receptors are the most widely expressed intracellular Ca2+ channels and both are regulated by sulphydryl reagents. In DT40 cells stably expressing single subtypes of mammalian IP3R, low concentrations of thimerosal, which oxidises thiols to form a thiomercurylethyl complex, increased the sensitivity of IP3-evoked Ca2+ release via IP3R1 and IP3R2, but inhibited IP3R3. Activation of IP3R is initiated by IP3 binding to the IP3-binding core (IBC, residues 224-604) and proceeds via re-arrangement of an interface between the IBC and suppressor domain (SD, residues 1-223). Thimerosal (100 µM) stimulated IP3 binding to the isolated N-terminal (NT, residues 1-604) of IP3R1 and IP3R2, but not to that of IP3R3. Binding of a competitive antagonist (heparin) or partial agonist (dimeric-IP3) to NT1 was unaffected by thimerosal, suggesting that the effect of thimerosal is specifically related to IP3R activation. IP3 binding to NT1 in which all Cys were replaced by Ala was insensitive to thimerosal, so too were NT1 in which Cys were replaced in either the SD or IBC. This demonstrates that thimerosal interacts directly with Cys in both the SD and IBC. Chimeric proteins in which the SD of the IP3R was replaced by the structurally related A-domain of a ryanodine receptor were functional, but thimerosal inhibited both IP3 binding to the chimeric NT and IP3-evoked Ca2+ release from the chimeric IP3R. This is the first systematic analysis of the effects of a sulphydryl reagent on each IP3R subtype. We conclude that thimerosal selectively sensitizes IP3R1 and IP3R2 to IP3 by modifying Cys residues within both the SD and IBC and thereby stabilizing an active conformation of the receptor.
    Biochemical Journal 01/2013; · 4.65 Impact Factor
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    ABSTRACT: Few inhibitors exist for CD38, a multifunctional enzyme catalyzing the formation and metabolism of the Ca(2+)-mobilizing second messenger cyclic adenosine 5'-diphosphoribose (cADPR). Synthetic, non-hydrolyzable ligands can facilitate structure-based inhibitor design. Molecular docking was used to reproduce the crystallographic binding mode of cyclic inosine 5'-diphosphoribose (N1-cIDPR) with CD38, revealing an exploitable pocket and predicting the potential to introduce an extra hydrogen bond interaction with Asp-155. The purine C-8 position of N1-cIDPR (IC50 276 µM) was extended with an amino or diaminobutane group and the 8-modified compounds were evaluated against CD38-catalyzed cADPR hydrolysis. Crystallography of an 8-amino N1-cIDPR:CD38 complex confirmed the predicted interaction with Asp-155, together with a second H-bond from a realigned Glu-146, rationalizing the improved inhibition (IC50 56 µM). Crystallography of a complex of cyclic ADP-carbocyclic ribose (cADPcR, IC50 129 µM) with CD38 illustrated that Glu-146 hydrogen bonds with the ligand N6-amino group. Both 8-amino N1-cIDPR and cADPcR bind deep in the active site reaching the catalytic residue Glu-226, and mimicking the likely location of cADPR during catalysis. Substantial overlap of the N1-cIDPR "northern" ribose monophosphate and the cADPcR carbocyclic ribose monophosphate regions suggests that this area is crucial for inhibitor design, leading to a new compound series of N1-inosine 5'-monophosphates (N1-IMPs). These small fragments inhibit hydrolysis of cADPR more efficiently than the parent cyclic compounds, with the best in the series demonstrating potent inhibition (IC50 = 7.6 µM). The lower molecular weight and relative simplicity of these compounds compared to cADPR make them attractive as a starting point for further inhibitor design.
    PLoS ONE 01/2013; 8(6):e66247. · 3.73 Impact Factor
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    ABSTRACT: Most animal cells express mixtures of the three subtypes of inositol 1,4,5-trisphosphate receptor (IP(3)R) encoded by vertebrate genomes. Activation of each subtype by different agonists has not hitherto been examined in cells expressing defined homogenous populations of IP(3)R. Here we measure Ca(2+) release evoked by synthetic analogues of IP(3) using a Ca(2+) indicator within the lumen of the endoplasmic reticulum of permeabilized DT40 cells stably expressing single subtypes of mammalian IP(3)R. Phosphorylation of (1,4,5)IP(3) to (1,3,4,5)IP(4) reduced potency by ∼100-fold. Relative to (1,4,5)IP(3), the potencies of IP(3) analogues modified at the 1-position (malachite green (1,4,5)IP(3)), 2-position (2-deoxy(1,4,5)IP(3)) or 3-position (3-deoxy(1,4,5)IP(3), (1,3,4,5)IP(4)) were similar for each IP(3)R subtype. The potency of an analogue, (1,4,6)IP(3), in which the orientations of the 2- and 3-hydroxyl groups were inverted, was also reduced similarly for all three IP(3)R subtypes. Most analogues of IP(3) interact similarly with the three IP(3)R subtypes, but the decrease in potency accompanying removal of the 1-phosphate from (1,4,5)IP(3) was least for IP(3)R3. Addition of a large chromophore (malachite green) to the 1-phosphate of (1,4,5)IP(3) only modestly reduced potency suggesting that similar analogues could be used to measure (1,4,5)IP(3) binding optically. These data provide the first structure-activity analyses of key IP(3) analogues using homogenous populations of each mammalian IP(3)R subtype. They demonstrate broadly similar structure-activity relationships for all mammalian IP(3)R subtypes and establish the potential utility of (1,4,5)IP(3) analogues with chromophores attached to the 1-position.
    PLoS ONE 01/2013; 8(1):e54877. · 3.73 Impact Factor
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    ABSTRACT: Inositol 1,4,5-trisphosphate receptors (IPR) are intracellular Ca channels. Most animal cells express mixtures of the three IPR subtypes encoded by vertebrate genomes. Adenophostin A (AdA) is the most potent naturally occurring agonist of IPR and it shares with IP the essential features of all IPR agonists, namely structures equivalent to the 4,5-bisphosphate and 6-hydroxyl of IP. The two essential phosphate groups contribute to closure of the clam-like IP-binding core (IBC), and thereby IPR activation, by binding to each of its sides (the α- and β-domains). Regulation of the three subtypes of IPR by AdA and its analogues has not been examined in cells expressing defined homogenous populations of IPR. We measured Ca release evoked by synthetic adenophostin A (AdA) and its analogues in permeabilized DT40 cells devoid of native IPR and stably expressing single subtypes of mammalian IPR. The determinants of high-affinity binding of AdA and its analogues were indistinguishable for each IPR subtype. The results are consistent with a cation-π interaction between the adenine of AdA and a conserved arginine within the IBC α-domain contributing to closure of the IBC. The two complementary contacts between AdA and the α-domain (cation-π interaction and 3″-phosphate) allow activation of IPR by an analogue of AdA (3″-dephospho-AdA) that lacks a phosphate group equivalent to the essential 5-phosphate of IP. These data provide the first structure-activity analyses of key AdA analogues using homogenous populations of all mammalian IPR subtypes. They demonstrate that differences in the Ca signals evoked by AdA analogues are unlikely to be due to selective regulation of IPR subtypes.
    PLoS ONE 01/2013; 8(2):e58027. · 3.73 Impact Factor
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    ABSTRACT: Inositol 1,4,5-trisphosphate [Ins(1,4,5)P3 1] mobilizes intracellular Ca2+ through the Ins(1,4,5)P3 receptor [InsP3R]. Although some progress has been made in the design of synthetic InsP3R partial agonists and antagonists, there are still few examples of useful small molecule competitive antagonists. A “multivalent” approach is explored and new dimeric polyphosphorylated aromatic derivatives were designed, synthesized and biologically evaluated. The established weak InsP3R ligand benzene 1,2,4-trisphosphate [Bz(1,2,4)P3 2] is dimerized through its 5-position in two different ways, first directly as the biphenyl derivative biphenyl 2,2�,4,4�,5,5�- hexakisphosphate, [BiPh(2,2�,4,4�,5,5��P6 8] and with its regioisomeric biphenyl 3,3�,4,4�,5,5�-hexakisphosphate [BiPh(3,3�,4,4�,5,5��P6 11]. Secondly, a linker motif is introduced in a flexible ethylene-bridged dimer (9) with its corresponding 1,2-bisphosphate dimer (10), both loosely analogous to the very weak antagonist 1,2-bis(2- aminophenoxy)ethane-N,N,N�,N�-tetraacetic acid (BAPTA 7). In permeabilized L15 fibroblasts overexpressing type 1 InsP3R, BiPh(2,2�,4,4�,5,5��P6 (8) inhibits Ins(1,4,5)P3-induced Ca2+ release in a apparently competitive fashion [IC50 187 nM] and the Bz(1,2,4)P3 dimer (9) is only slightly weaker [IC50 380 nM]. Compounds were also evaluated against type I Ins(1,4,5)P3 5-phosphatase. All compounds are resistant to dephosphorylation, with BiPh(2,2�,4,4�,5,5��P6 (8), being the most effective inhibitor of any biphenyl derivative synthesized to date [IC50 480 nM] and the Bz(1,2,4)P3 ethylene dimer (9) weaker [IC50 3.55 �M]. BiPh(3,3�,4,4�,5,5��P6 (11) also inhibits 5-phosphatase [IC50 730 nM] and exhibits unexpected Ca2+ releasing activity [EC50 800 nM]. Thus, relocation of only a single mirrored phenyl phosphate group in (11) from that of antagonist (8) does not markedly change enzyme inhibitory activity, but elicits a dramatic switch in Ca2+-releasing activity. Such new agents demonstrate the power of the multivalent approach and may be useful to investigate the chemical biology of signaling through InsP3R and as templates for further design.
    ASP Messenger. 12/2012; 1:167-181.
  • Messenger. 12/2012;
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    ABSTRACT: The myo-inositol phosphates (InsPs) are specific signalling metabolites ubiquitous in eukaryotic cells. Although Ins(1,3,4,5,6)P(5) is the second most abundant member of the InsPs family, its certain biological roles are far from being elucidated, in part due to the large number of species formed by Ins(1,3,4,5,6)P(5) in the presence of metal ions. In light of this, we have strived in the past to make a complete and at the same time "biological-user-friendly" description of the Ins(1,3,4,5,6)P(5) chemistry with mono and multivalent cations. In this work we expand these studies focusing on the inframolecular aspects of its protonation equilibria and the microscopic details of its coordination behaviour towards biologically relevant metal ions. We present here a systematic study of the Ins(1,3,4,5,6)P(5) intrinsic acid-base processes, in a non-interacting medium, and over a wide pH range, analyzing the (31)P NMR curves by means of a model based on the Cluster Expansion Method. In addition, we have used a computational approach to analyse the energetic and structural features of the protonation and conformational changes of Ins(1,3,4,5,6)P(5), and how they are influenced by the presence of two physiologically relevant cations, Na(+) and Mg(2+).
    Dalton Transactions 11/2012; · 3.81 Impact Factor

Publication Stats

5k Citations
1,655.88 Total Impact Points

Institutions

  • 1991–2014
    • University of Bath
      • Department of Pharmacy and Pharmacology
      Bath, England, United Kingdom
  • 2013
    • University Medical Center Hamburg - Eppendorf
      Hamburg, Hamburg, Germany
  • 2005–2013
    • Hokkaido University
      • • Faculty of Pharmaceutical Sciences
      • • Graduate School of Pharmaceutical Sciences
      Sapporo-shi, Hokkaido, Japan
  • 1990–2013
    • University of Cambridge
      • Department of Pharmacology
      Cambridge, ENG, United Kingdom
  • 2012
    • Smithsonian Tropical Research Institute
      Ciudad de Panamá, Panamá, Panama
  • 1993–2012
    • Imperial College London
      • • Faculty of Medicine
      • • Section of Investigative Medicine
      • • Division of Diabetes, Endocrinology and Metabolism
      • • Section of Cell Biology
      London, ENG, United Kingdom
  • 2009
    • Università degli Studi di Brescia
      • Dipartimento di Scienze Biomediche e Biotecnologie
      Brescia, Lombardy, Italy
  • 1995–2009
    • University of Hamburg
      • • Center for Experimental Medicine
      • • Institute of Biochemistry and Molecular Biology
      Hamburg, Hamburg, Germany
  • 2005–2007
    • Université Libre de Bruxelles
      • Institute of Interdisciplinary Research in human and molecular Biology (IRIBHM)
      Brussels, BRU, Belgium
  • 2002
    • University of Oxford
      Oxford, England, United Kingdom
  • 1999
    • University of Colorado at Boulder
      • Institute for Behavioral Genetics (IBG)
      Boulder, CO, United States
  • 1997
    • Kyushu University
      • Faculty of Dental Science
      Fukuoka-shi, Fukuoka-ken, Japan
  • 1996
    • The School of Pharmacy
      • Pharmacology
      Bath, England, United Kingdom
    • Imperial College Healthcare NHS Trust
      Londinium, England, United Kingdom
  • 1985–1994
    • University of Leicester
      • • Department of Cell Physiology and Pharmacology
      • • Department of Chemistry
      Leicester, ENG, United Kingdom