Total synthesis of the protein phosphatase inhibitor okadaic acid

Ley, Steven V.; Humphries, Alexander C.; Eick, Holger; Downham, Robert; Ross, Andrew R. S.; Boyce, Richard J.; Pavey, John B. J.; Pietruszka, Jörg

doi:10.1039/a807957i

Cited by 74 publications

(70 citation statements)

References 36 publications

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“…One of the major tau phosphatases, PP-2A, is capable of dephosphorylation of many abnormally phosphorylated sites on tau [166] and inhibition of PP-2A by okadaic acid (22) [167,168] causes an upregulation of activity of several kinases and a hyperphosphorylation of tau similar to that seen in AD brain [113]. Similar inhibition of PP-2B by cyclosporine produced little effect.…”

Section: Tau Phosphatasesmentioning

confidence: 85%

Tau Therapeutic Strategies for the Treatment of Alzheimers Disease

Churcher

2006

CTMC

123

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The two classical pathological hallmarks of Alzheimer's disease are deposits of aggregated beta-amyloid (Abeta) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition to Abeta pathology, an invariant trait of Alzheimer's disease, disruption of tau processing is a necessary event in the neurotoxic cascade which eventually leads to neuronal death and subsequent dementia. Tau is a neuronal, microtubule-bound protein which becomes hyperphosphorylated as a result of an imbalance of the kinase and phosphatase activities which normally tightly regulate its phosphorylation. In addition to this pathogenic hyperphosphorylation, tau dissociates from microtubules and self-aggregates to form insoluble oligomers which progress to the macroscopic tangles evident in post mortem Alzheimer's disease tissue. Subsequent toxicity may ensue either as a direct toxic effect of free tau oligomers or as a result of altered microtubule-dependent processes. In order to intervene pharmacologically in this disease process, much effort has been expended in order to identify and inhibit the kinases responsible for pathogenic hyperphosphorylation and many candidate kinases have been investigated including glycogen synthase kinase (GSK-3), cyclin-dependant kinase-5 (Cdk-5), MAPK family members (extracellular signal-regulated kinases 1 and 2 [Erk-1 and 2], MEK [MAP kinase kinase], c-Jun NH(2)-terminal kinases (JNKs) and p38), casein kinase, calcium calmodulin-dependant kinase II (CaMK-II), microtubule affinity regulating kinase (MARK), protein kinase A (PKA/cAMP-dependant protein kinase) and others. Focus has also fallen upon the role of the phosphatases responsible for dephosphorylation of tau. This review will describe the tau-related etiology of Alzheimer's disease and other tauopathies as well as the therapeutic strategies to inhibit the hyperphosphorylation of tau.

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Section: Tau Phosphatasesmentioning

confidence: 85%

Tau Therapeutic Strategies for the Treatment of Alzheimers Disease

Churcher

2006

CTMC

123

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“…In the total synthesis of the protein phosphatase inhibitor okadaic acid, Ley et al described a complex alkynylation reaction with the mannose derivative 5 (Scheme 13) [111]. This compound was first protected with a sulfide in the anomeric position which was later oxidized to the corresponding sulfone as an activating group.…”

Section: Coupling Between An Electrophilic Anomeric Carbon and A Nuclmentioning

confidence: 99%

The synthesis of d-C-mannopyranosides

Choumane¹,

Banchet²,

Probst³

et al. 2010

Comptes Rendus. Chimie

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“…The reagent TPAP/NMO/PMS/ CH 3 CN effected a diol to lactone step in the synthesis of the antitumour agent entclavilactone B [358] and the antileukemic agents (−)-eriolangin and (−)-eriolanin [359]. During synthesis of the protein phosphatase inhibitor okadaic acid three oxidations with TPAP/NMO/PMS/CH 2 Cl 2 were used, two of primary alcohol to aldehydes and one of a diol to a lactone [109], and in the synthesis of the immunoadjuvant QS-21A api a diol-to-lactone step is involved [360], as in the case of the lypophilic macrolide rapamycin (cf. 1.11) [181].…”

Section: Specific Examplesmentioning

confidence: 99%

“…During synthesis of the protein phosphatase inhibitor okadaic acid three oxidations with TPAP/NMO/PMS/CH 2 Cl 2 were used, two of a primary alcohol to aldehydes and one of a diol to a lactone [109]; the reagent was used in the synthesis of a fragment of the antibiotic sorangicin A [110].…”

Section: Natural Product/pharmaceutical Syntheses Involving Primary Amentioning

confidence: 99%

Oxidation of Alcohols, Carbohydrates and Diols

Griffith

2009

Catalysis by Metal Complexes

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This is one of the most important classes of oxidation effected by Ru complexes, particularly by RuO 4 , [RuO 4 ] − , [RuO 4 ] 2− and RuCl 2 (PPh 3 ) 3 , though in fact most Ru oxidants effect these transformations. The chapter covers oxidation of primary alcohols to aldehydes (section 2.1), and to carboxylic acids (2.2), and of secondary alcohols to ketones (2.3). Oxidation of primary and secondary alcohol functionalities in carbohydrates (sugars) is dealt with in section 2.4, then oxidation of diols and polyols to lactones and acids (2.5). Finally there is a short section on miscellaneous alcohol oxidations in section 2.6.In this chapter the first of the two most important categories of oxidations catalysed by Ru complexes (the other being alkene and alkyne oxidations in Chapter 3) are considered. The approach in this and subsequent chapters differs from that of Chapter 1, concentrating here on the substrate rather than on the oxidant. The text is divided into the categories of alcohols and their oxidations. There are summaries in section 2.3.6 of systems of limited applicability which are mentioned only in Chapter 1, and in section 2.3.7 of large-scale (>1 g) oxidations.The first oxidations of alcohols by stoicheiometric RuO 4 /H 2 O were reported in 1958, of primary alcohols to aldehydes or carboxylic acids and secondary alcohols to ketones [1]. The first Ru-catalysed oxidation of an alcohol was reported in 1965 when Parikh and Jones used RuO 2 /aq. Na(IO 4 )/CCl 4 1 ( Table 2.3) [2] to oxidise secondary alcohol groups in carbohydrates.Oxidation of alcohols is the most frequently reviewed topic for Ru-catalysed oxidations [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Mechanisms of alcohol oxidation by Ru complexes have been reviewed [21].

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Total synthesis of the protein phosphatase inhibitor okadaic acid

Cited by 74 publications

References 36 publications

Tau Therapeutic Strategies for the Treatment of Alzheimers Disease

Tau Therapeutic Strategies for the Treatment of Alzheimers Disease

The synthesis of d-C-mannopyranosides

Oxidation of Alcohols, Carbohydrates and Diols

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