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Nigel S. Watson - One of the best experts on this subject based on the ideXlab platform.

David M Hodgson - One of the best experts on this subject based on the ideXlab platform.

  • Evolution of a Cycloaddition–Rearrangement Approach to the Squalestatins: A Quarter-Century Odyssey
    Synlett, 2020
    Co-Authors: Hasanain A. A. Almohseni, David M Hodgson
    Abstract:

    The highs, lows, and diversions of a journey leading to two syntheses of 6,7-dideoxySqualestatin H5 is described. Both syntheses relied on highly diastereoselective n-alkylations of a tartrate acetonide enolate and subsequent oxidation–hydrolysis to provide an asymmetric entry to β-hydroxy-α-ketoester motifs. The latter were differentially elaborated to diazoketones which underwent stereo- and regioselective Rh(II)-catalysed cyclic carbonyl ylide formation–cycloaddition and then acid-catalysed transketalisation to generate the 2,8-dioxabicyclo[3.2.1]octane core of the Squalestatins/zaragozic acids at the correct tricarboxylate oxidation level. The unsaturated side chain was either protected with a bromide substituent during the transketalisation or introduced afterwards by a stereoretentive Ni-catalyzed Csp3–Csp2 cross-electrophile coupling. 1 Introduction 2 Racemic Model Studies to the Squalestatin/Zaragozic Acid Core 3 Asymmetric Model Studies to a Keto α-Diazoester 3.1 Dialkyl Squarate Desymmetrisation 3.2 Tartrate Alkylation 3.2.1 Further Studies on Seebach’s Alkylation Chemistry  4 Failure at the Penultimate Step to DDSQ  5 Second-Generation Approach to DDSQ: A Bromide Substituent Strategy  5.1 Stereoselective Routes to E-Alkenyl Halides via β-Oxido Phosphonium Ylides  5.2 Back to DDSQ Synthesis 6 An Alternative Strategy to DDSQ: By Cross-Electrophile Coupling 7 Alkene Ozonolysis in the Presence of Diazo Functionality: Accessing α-Ketoester Intermediates 8 Summary

  • squarate desymmetrisation ozonolysis as an approach to β substituted α ketosuccinates and Squalestatin synthesis
    Tetrahedron, 2019
    Co-Authors: Ho Sintim, Dc Harling, Anne Valade, David M Hodgson
    Abstract:

    Abstract Silylated tertiary alcohols from 1,2-addition of alkyllithiums to dialkyl squarates undergo alkene ozonolysis to give β-substituted-α-keto-β-(silyloxy)succinates. With 3-(triethylsilyloxy)butyllithium the methodology was applied to the 2,8-dioxabicyclo[3.2.1]octane core of the Squalestatins. Enantioselective 1,2-addition to di-tert-butyl squarate using butyllithium or diethylzinc/Ti(iPrO)4 in the presence of chiral ligands (such as bisoxazolines or camphorsulfonamides, respectively) gave the corresponding tertiary alcohols in up to 67.5:32.5 er.

  • Synthetic and computational studies on the tricarboxylate core of 6,7-dideoxySqualestatin H5 involving a carbonyl ylide cycloaddition-rearrangement
    Organic & biomolecular chemistry, 2010
    Co-Authors: David M Hodgson, Carol Villalonga-barber, Jonathan M. Goodman, Silvina C. Pellegrinet
    Abstract:

    Reaction of diazodiketoesters 17 and 28 with methyl glyoxylate in the presence of catalytic rhodium(II) acetate generates predominantly the 6,8-dioxabicyclo[3.2.1]octanes 29 and 30, respectively. Acid-catalysed rearrangement of the corresponding alcohol 31 favours, at equilibrium, the 2,8-dioxabicyclo[3.2.1]octane skeleton 33 of the Squalestatins–zaragozic acids. Force field calculations on the position of the equilibrium gave misleading results. DFT calculations were correct in suggesting that the energy difference between 31 and 33 should be small, but did not always suggest the right major product. Calculation of the NMR spectra of the similar structures could be used to assign the isomers with a high level of confidence.

  • selectivity in the cycloadditions of carbonyl ylides with glyoxylates an approach to the zaragozic acids Squalestatins
    Journal of The Chemical Society-perkin Transactions 1, 2000
    Co-Authors: David M Hodgson, James M Bailey, Carolina Villalongabarber, Michael G B Drew, Timothy Harrison
    Abstract:

    Reaction of diazodiketoester 8 with glyoxylates in the presence of catalytic rhodium(II) acetate generates 6,8-dioxabicyclo[3.2.1]octanes 9 and 11 in good yield. Elaboration of 9 provides a suitable alcohol 25 for acid-catalysed rearrangement to give the 2,8-dioxabicyclo[3.2.1]octane skeleton 26 of the zaragozic acids—Squalestatins. More substituted diazodiketoesters 36 and 40 also undergo highly regio- and diastereoselective cycloaddition with glyoxylates to give the cycloadducts 41, 43 and 44.

  • Studies towards a stereocontrolled synthesis of the tricarboxylate core of the zaragozic acids–Squalestatins by a cycloaddition–rearrangement strategy
    Tetrahedron Letters, 2000
    Co-Authors: David M Hodgson, Carol Villalonga-barber
    Abstract:

    Abstract Reaction of diazoketodiester 11 with methyl glyoxylate in toluene in the presence of catalytic rhodium(II) acetate gives predominantly the 6,8-dioxabicyclo[3.2.1]octane 13. Acid-catalysed rearrangement of the corresponding alcohol 14 favours at equilibrium the 2,8-dioxabicyclo[3.2.1]octane skeleton 15 of the zaragozic acids–Squalestatins.

Panayiotis A. Procopiou - One of the best experts on this subject based on the ideXlab platform.

  • The Squalestatins: cleavage of the bicyclic core via the novel 6,8-dioxabicyclo[3.2.1]octane ring system
    Journal of the Chemical Society Perkin Transactions 1, 1995
    Co-Authors: Panayiotis A. Procopiou, Philip J. Sidebottom, Anton R. P. Srikantha, E. J. Bailey, Graham G. A. Inglis, Michael George Lester, C. Chan, Nigel S. Watson
    Abstract:

    Squalestatin S1 1 has been converted into its 4,7-bis(2-methoxyethoxymethyl)ether 4,5-dimethyl ester 11 and thence to its 3-(tert-butoxycarbonyl)amino derivative 12via a Schmidt degradation. Acid-catalysed hydrolysis of 12 brought about a molecular rearrangement of the 2,8-dioxa- to the novel 6,8-dioxa-bicyclo[3.2.1]octane ring system 3. Oxidation of 3 followed by methanolysis gave the novel spiroketal 17. Treatment of 3 with trimethyl phosphonoacetate gave the acyclic derivative 18.

  • The Squalestatins: effects of changes at the allylic centre in the C1 sidechain
    Bioorganic & Medicinal Chemistry Letters, 1994
    Co-Authors: Michael G. Lester, Stephen J. Spooner, Michael A Snowden, Panayiotis A. Procopiou, Gary L. Evans, Richard A. Henson, Meenu Sareen, Anton A.p. Srikantha, Nigel S. Watson
    Abstract:

    Abstract The C4′ acetoxy group in Squalestatin 2a has been replaced by alkoxy, acyloxy and acetamido groups. The ethers 5b, 5c, 5e and 5g retain SQS inhibitory activity equivalent to that of 2a and are metabolically more stable. All other compounds tested are significantly less active.

  • Structurally simplified Squalestatins: monocyclic 1,3-dioxane analogues.
    Bioorganic & Medicinal Chemistry Letters, 1994
    Co-Authors: Peter J Sharratt, Julie L. Hutson, Graham G. A. Inglis, Panayiotis A. Procopiou, Michael George Lester, Nigel S. Watson
    Abstract:

    Abstract Monocyclic analogues of Squalestatin 1 based on a 1,3-dioxane ring were prepared and evaluated for their ability to inhibit squalene synthase in vitro. The compound 16a possessing a 4,6-dimethyloctenoyloxymethyl group at C4 and a carboxamide at C2 showed similar inhibitory activity to 1.

  • A synthetic approach to Squalestatin 1
    Journal of the Chemical Society Chemical Communications, 1993
    Co-Authors: Hesham Abdel-rahman, Joseph P. Adams, Alastair L. Boyes, M. J. Kelly, Darren J. Mansfield, Panayiotis A. Procopiou, Stanley M. Roberts, Deborah H. Slee, Nigel S. Watson
    Abstract:

    D-(+)-1,6-Anhydrogalactose 4 has been converted into the γ-lactone 16en route to Squalestatin 1.

  • Synthesis of the bicyclic core structure of Squalestatin 1
    Journal of the Chemical Society Chemical Communications, 1993
    Co-Authors: Hesham Abdel-rahman, Philip J. Sidebottom, Joseph P. Adams, Alastair L. Boyes, M. J. Kelly, Darren J. Mansfield, Panayiotis A. Procopiou, Stanley M. Roberts, Deborah H. Slee, Vladimir Šik
    Abstract:

    The butenolides 2 and 3 have been converted into the dioxabicyclo[3.2.1] loctane derivative 15, a late-stage precursor to Squalestatin 1 16.

Thomas A. Kocarek - One of the best experts on this subject based on the ideXlab platform.

  • Transcriptional Regulation of Cytosolic Sulfotransferase 1C2 by Intermediates of the Cholesterol Biosynthetic Pathway in Primary Cultured Rat Hepatocytes s
    2015
    Co-Authors: Elizabeth A. Rondini, Asmita Pant, Thomas A. Kocarek
    Abstract:

    Cytosolic sulfotransferase 1C2 (SULT1C2) is expressed in the kidney, stomach, and liver of rats; however, the mechanisms regulating expression of this enzyme are not known.We evaluated transcriptional regulation of SULT1C2 by mevalonate (MVA)-derived intermediates in primary cultured rat hepatocytes using several cholesterol synthesis inhibitors. Blocking production of mevalonate with the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor pravastatin (30mM), reducedSULT1C2mRNAcontent by ∼40%whereas the squalene synthase inhibitor Squalestatin (SQ1, 0.1 mM), which causes accumulation of nonsterol isoprenoids, increased mRNA content by 4-fold. Treatment with MVA (10 mM) strongly induced SULT1C2 mRNA by 12-fold, and this effect was blocked by inhibiting squalene epoxidase but not by more distal cholesterol inhibitors, indicating the effects of MVA are mediate

  • Conserved effects of squalene synthase inhibitors on gene expression changes in primary cultured rat and mouse hepatocytes (1148.2)
    The FASEB Journal, 2014
    Co-Authors: Elizabeth A. Rondini, Zofia Duniec-dmuchowski, Alan A. Dombkowski, Thomas A. Kocarek
    Abstract:

    Squalene synthase inhibitors, such as Squalestatin 1 (SQ1), are cholesterol-lowering drugs that block the first committed step in sterol biosynthesis. Unlike statins (e.g., pravastatin), inhibition...

  • Suppression of CYP2B induction by alendronate-mediated farnesyl diphosphate synthase inhibition in primary cultured rat hepatocytes.
    Drug metabolism and disposition: the biological fate of chemicals, 2008
    Co-Authors: Nancy M. Jackson, Thomas A. Kocarek
    Abstract:

    We previously reported that Squalestatin 1-mediated induction of CYP2B expression is attributable to squalene synthase inhibition and accumulation of an endogenous isoprenoid(s) that is capable of activating the constitutive androstane receptor. To determine whether Squalestatin 1-mediated CYP2B induction is strictly dependent on the biosynthesis of farnesyl pyrophosphate (FPP), the substrate for squalene synthase, the effects of alendronate, a nitrogen-containing bisphosphonate inhibitor of farnesyl diphosphate synthase, on basal, Squalestatin 1-inducible, and phenobarbital-inducible CYP2B expression in primary cultured rat hepatocytes were assessed. Alendronate treatment alone had no effect on CYP2B or CYP3A mRNA expression in the hepatocyte cultures, but alendronate cotreatment completely suppressed Squalestatin 1-mediated CYP2B mRNA induction at concentrations (60 and 100 μM) that effectively inhibited cellular farnesyl diphosphate synthase activity, as assessed by reductions of Squalestatin 1-mediated FPP accumulation, and that were not toxic to the cells, as indicated by a lack of effect on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide activity. Alendronate cotreatment also partially suppressed phenobarbital-inducible CYP2B expression, and this suppressive effect was attenuated by additional cotreatment with the upstream pathway inhibitor, pravastatin. These findings not only demonstrate that Squalestatin 1-mediated CYP2B induction cannot occur in the absence of FPP biosynthesis but also indicate that one or more upstream isoprenoids, possibly isopentenyl pyrophosphate and/or dimethylallyl pyrophosphate, function to antagonize the CYP2B induction process.

  • Squalestatin 1-Inducible Expression of Rat CYP2B: Evidence That an Endogenous Isoprenoid Is an Activator of the Constitutive Androstane Receptor
    Molecular pharmacology, 2002
    Co-Authors: Thomas A. Kocarek, Nancy A. Mercer-haines
    Abstract:

    Because our previous studies indicated that Squalestatin 1 treatment induces CYP2B expression in primary cultures of rat hepatocytes as a direct consequence of squalene synthase inhibition, we investigated possible underlying mechanisms. Cotransfection of cultured Sprague-Dawley male rat hepatocytes with each of the three sterol regulatory element binding protein (SREBP) transcription factors failed to induce luciferase expression from a Squalestatin 1-responsive CYP2B1 reporter plasmid. Squalestatin 1 treatment of primary hepatocyte cultures from male Wistar-Kyoto rats produced a greater induction of CYP2B mRNA than occurred in cultures from female rats, consistent with the previously demonstrated response dimorphism that has been attributed to differences in constitutive androstane receptor (CAR) levels. Cotransfection of female Wistar-Kyoto rat hepatocyte cultures with plasmid expressing either mouse or rat CAR restored Squalestatin 1-inducible CYP2B1-reporter expression. Cotransfection of Sprague-Dawley rat hepatocyte cultures with plasmid expressing rat CAR lacking the C-terminal AF-2 subdomain inhibited Squalestatin 1-inducible CYP2B1-reporter expression. Squalestatin 1-mediated CYP2B mRNA induction in rat hepatocyte cultures was completely abolished by pretreatment with the 3-hydroxymethyl-3-glutaryl CoA reductase inhibitor pravastatin and was rescued by mevalonate supplementation, whereas phenobarbital-mediated induction was unaffected by these treatments. Finally, direct addition oftrans,trans-farnesol to the culture medium caused the rapid induction of CYP2B mRNA. These results indicate that Squalestatin 1 treatment induces CYP2B expression, not by inhibiting sterol synthesis and activating SREBPs, but by evoking the accumulation of an endogenous isoprenoid and activating CAR.

  • Squalestatin 1-Inducible Expression of Rat CYP2B: Evidence That an Endogenous Isoprenoid Is an Activator of the Constitutive Androstane Receptor
    2002
    Co-Authors: Thomas A. Kocarek, Nancy A. Mercer-haines
    Abstract:

    Because our previous studies indicated that Squalestatin 1 treatment induces CYP2B expression in primary cultures of rat hepatocytes as a direct consequence of squalene synthase inhibition, we investigated possible underlying mechanisms. Cotransfection of cultured Sprague-Dawley male rat hepato-cytes with each of the three sterol regulatory element binding protein (SREBP) transcription factors failed to induce luciferase expression from a Squalestatin 1-responsive CYP2B1 reporter plasmid. Squalestatin 1 treatment of primary hepatocyte cul-tures from male Wistar-Kyoto rats produced a greater induction of CYP2B mRNA than occurred in cultures from female rats, consistent with the previously demonstrated response dimor-phism that has been attributed to differences in constitutive androstane receptor (CAR) levels. Cotransfection of femal

Russell J. Cox - One of the best experts on this subject based on the ideXlab platform.

  • Reengineering the programming of a functional domain of an iterative highly reducing polyketide synthase
    RSC Advances, 2020
    Co-Authors: Oliver Piech, Russell J. Cox
    Abstract:

    A structural model of the enoyl reductase (ER) catalytic domain of the fungal highly-reducing polyketide synthase Squalestatin tetraketide synthase (SQTKS) was developed. Simulated docking of substrates and inhibitors allowed the definition of active site residues involved in catalysis and substrate selectivity. These were investigated in silico with the aim of extending the substrate scope. Residues were identified which limit the substrate selectivity of the SQTKS ER, and these were mutated and the engineered ER domain assayed in vitro. Significant changes to the programming of the mutant SQTKS ER domains were observed allowing the processing of longer and more methylated substrates.

  • In vitro kinetic study of the Squalestatin tetraketide synthase dehydratase reveals the stereochemical course of a fungal highly reducing polyketide synthase
    Chemical communications (Cambridge England), 2017
    Co-Authors: Emma Liddle, Thomas J. Simpson, Alan Scott, Li-chen Han, David Ivison, Christine L. Willis, Russell J. Cox
    Abstract:

    Six potential diketide substrates for the Squalestatin tetraketide synthase (SQTKS) dehydratase (DH) domain were synthesised as N-acetyl cysteamine thiolesters (SNAC) and tested in kinetic assays as substrates with an isolated DH domain. 3R-3-hydroxybutyryl SNAC 3R-16 was turned over by the enzyme, but its enantiomer was not. Of the four 2-methyl substrates only 2R,3R-2-methyl-3-hydroxybutyryl SNAC 2R,3R-8 was a substrate. Combined with stereochemical information from the isolated SQTKS enoyl reductase (ER) domain, our results provide a near complete stereochemical description of the first cycle of beta-modification reactions of a fungal highly reducing polyketide synthase (HR-PKS). The results emphasise the close relationship between fungal HR-PKS and vertebrate fatty acid synthases (vFAS).

  • Identification of genes encoding Squalestatin S1 biosynthesis and in vitro production of new Squalestatin analogues
    Chemical communications (Cambridge England), 2016
    Co-Authors: B. Bonsch, Colin M. Lazarus, Thomas J. Simpson, V. Belt, C. Bartel, N. Duensing, M. Koziol, Andy M. Bailey, Russell J. Cox
    Abstract:

    A gene cluster responsible for the biosynthesis of Squalestatin S1 (SQS1, 1) was identified by full genome sequencing of two SQS1-producing ascomycetes: Phoma sp. C2932 and unidentified fungus MF5453. A transformation protocol was established and a subsequent knockout of one PKS gene from the cluster led to loss of SQS1 production and enhanced concentration of an SQS1 precursor. An acyltransferase gene from the cluster was expressed in E. coli and the expressed protein MfM4 shown to be responsible for loading acyl groups from CoA onto the Squalestatin core as the final step of biosynthesis. MfM4 appears to have a broad substrate selectivity for its acyl CoA substrate, allowing the in vitro synthesis of novel Squalestatins.

  • Mutation of key residues in the C-methyltransferase domain of a fungal highly reducing polyketide synthase.
    Molecular bioSystems, 2010
    Co-Authors: Elizabeth Skellam, Deirdre Hurley, Colin M. Lazarus, Thomas J. Simpson, Jack R. Davison, Russell J. Cox
    Abstract:

    Site directed mutations of the C-methyltransferase domain of Squalestatin tetraketide synthase were made in an attempt to alter the methylation pattern of the synthase expressed in vivo: mutation resulted in either no effect or in complete abrogation of polyketide production.