Synthesis of anti-tumour phosphatidylinositol analogues from glucose by the use of ring-closing olefin metathesis

Andresen, Thomas Lars; Skytte, Dorthe Mondrup; Madsen, Robert

doi:10.1039/b411021h

Cited by 30 publications

(21 citation statements)

References 45 publications

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“…Both phospholipase C and PI3K exhibit this enhanced activity with interfacial substrates / inhibitors. 35,36 Since the 3-deoxy-diC 8 PI molecules, unlike the longer acyl chain synthetic 3-deoxy-PI molecules examined previously, 7,14 can exist as both monomers and micelles in solution, we require information on the physical state of the short chain PI analogues, notably their CMC as well as roughly what size micelles they form. This is also critical information for determining the distribution of the 3-deoxy-diC 8 PI species in cells at concentrations where they may cause cell death.…”

Section: Characterization Of Dic 8 Pi Compoundsmentioning

confidence: 99%

Insights into the Structural Specificity of the Cytotoxicity of 3-Deoxyphosphatidylinositols

et al. 2008

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D-3-Deoxy-phosphatidylinositol derivatives have cytotoxic activity against various human cancer cell lines. These phosphatidylinositols have a potentially wide array of targets in the phosphatidylinositol-3-kinase (PI3K)/Akt signaling network. To explore the specificity of these types of molecules, we have synthesized D-3-deoxy-dioctanoylphosphatidylinositol (D-3-deoxydiC 8 PI), D-3,5-dideoxy-diC 8 PI and D-3-deoxy-dioctanoylphosphatidylinositol-5-phosphate and their enantiomers, characterized their aggregate formation by novel high resolution field cycling 31 P NMR, and examined their susceptibility to phospholipase C (PLC) and their effects on the catalytic activity of PI3K and PTEN against diC 8 PI and dioctanoylphosphatidylinositol-3-phosphate substrates, respectively, as well as their ability to induce the death of the U937 human leukemic monocyte lymphoma cells. Of these molecules, only D-3-deoxy-diC 8 PI was able to promote cell death; it did so with an IC 50 of 40 μM, well below the CMC of 0.4 mM. Under these conditions, there was little inhibition of PI3K or PTEN observed in assays of recombinant enzymes (although the complete series of deoxy-PI compounds did provide insights into ligand binding by PTEN). The D-3-deoxydiC 8 PI was a poor substrate and not an inhibitor of the PLC enzymes. The in vivo results are consistent with the current thought that the PI analogue acts on Akt1 since the transcription initiation factor eIF4e, which is a downstream signaling target of the PI3K/Akt pathway, exhibited reduced phosphorylation on Ser209. Phosphorylation of Akt1 on Ser473, but not Thr308, was reduced. Since the potent cytotoxicity for U937 cells is completely lost with the L-3-deoxy-diC 8 PI as well as with modification of the hydroxyl group at the inositol C5 (either replacing the -OH with a hydrogen or phosphorylating it) in D-3-deoxy-diC 8 PI, both chirality of the phosphoinositol moiety and the hydroxyl group at C5 are major determinants of 3-deoxy-PI binding to its target in cells.

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Section: Characterization Of Dic 8 Pi Compoundsmentioning

confidence: 99%

Insights into the Structural Specificity of the Cytotoxicity of 3-Deoxyphosphatidylinositols

et al. 2008

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“…The PTEN active site is rich in charged residues that could interact differently with modified inositol compounds. Limited modeling suggests how PI(1,3,4,5)P 3 might bind in the PTEN active site, but there is no structure to confirm this arrangement, or to suggest where any hydrophobic segments, which are present in all the optimized 3-deoxy-PI inhibitors [22–24], might bind. Given its extreme functional importance, understanding how different substrate-like molecules bind to PTEN is critical.…”

Section: Introductionmentioning

confidence: 99%

Understanding the stereospecific interactions of 3-deoxyphosphatidylinositol derivatives with the PTEN phosphatase domain

Wang

Yang

Mottamal

et al. 2010

Journal of Molecular Graphics and Modelling

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PTEN is an important control element of PI3K/AKT signaling involved in controlling the processes of embryonic development, cell migration and apoptosis. While its dysfunction is implicated in a large fraction of cancers, PTEN activity in the same pathway may also contribute to metabolic syndromes such as diabetes. In those cases, selective inhibitors of PTEN may be useful. A new class of chiral PTEN inhibitors based on the 3-deoxy-phosphatidylinositol derivatives was recently identified [Wang et al. (2008) J. Am. Chem. Soc. 130, 7746]. However, lack of detailed understanding of protein-ligand interactions has hampered efforts to develop effective agonists or antagonists of PTEN. Here, we use computational modeling to characterize the interactions of the diverse 3-deoxyphosphatidylinositol inhibitors with the PTEN protein. We show that, while each of the compounds binds with the inositol headgroup inserting into the proposed active site of the PTEN phosphatase domain, hydrogen bonding restrictions lead to distinct binding geometries for ligand pairs of opposite chirality. We furthermore demonstrate that the binding modes differ primarily in the orientation of acyl tails of the ligands and that the activity of the compounds is primarily controlled by the effectiveness of tail-protein contacts. These findings are confirmed by binding affinity calculations which are in good agreement with experiment. Finally, we show that while more potent D-series ligands bind in a manner similar to that of the native substrate, an alternate hydrophobic pocket suitable for binding the opposite chirality L-series inhibitors exists, offering the possibility of designing highly selective PTEN- targeting compounds.

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“…The reason why the chloride reagent gives better selectivity than the bromide reagent is unclear, but similar behaviour has been observed before in related systems. 40 Triol 3a was treated with 2,2-dimethoxypropane and catalytic camphorsulfonic acid, giving the five-membered ring acetonide 4 in a poor 33% yield along with two more products, which were identified as the six-membered (5) and seven-membered (6) ring isomers, respectively (4:5:6; 10:2:5). The regiochemical assignment of 4-6 was made based on 13 C NMR chemical shifts of the acetonide methyl groups and quaternary carbons.…”

Section: Resultsmentioning

confidence: 99%

Carbasugar analogues of galactofuranosides: β-O-linked derivatives and towards β-S-linked derivatives

Frigell¹,

Eriksson²,

Cumpstey³

2011

Carbohydrate Research

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Synthesis of anti-tumour phosphatidylinositol analogues from glucose by the use of ring-closing olefin metathesis

Cited by 30 publications

References 45 publications

Insights into the Structural Specificity of the Cytotoxicity of 3-Deoxyphosphatidylinositols

Insights into the Structural Specificity of the Cytotoxicity of 3-Deoxyphosphatidylinositols

Understanding the stereospecific interactions of 3-deoxyphosphatidylinositol derivatives with the PTEN phosphatase domain

Carbasugar analogues of galactofuranosides: β-O-linked derivatives and towards β-S-linked derivatives

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