Fostriecin

Jong, R.S. de; Vries, Ege de; Mulder, Nanno

doi:10.1097/00001813-199706000-00001

Cited by 43 publications

(22 citation statements)

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“…[62] Most probably the triene moiety in fostriecin and cytostatin is responsible for the instability of the natural products upon storage. Thus, the finding that it may be replaced by simpler structural elements without loss of biological activity is of particular importance for the design of more stable but still active analogues.…”

Section: Biological Evaluation Of Cytostatin Analoguesmentioning

confidence: 99%

Total Synthesis and Biological Evaluation of the Protein Phosphatase 2A Inhibitor Cytostatin and Analogues

Bialy

Waldmann

2004

Chemistry A European J

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The total synthesis of the natural product cytostatin is described which inhibits protein phosphatase 2A. Cytostatin has anti-metastatic properties and induces apoptosis. On the basis of this synthesis the relative and absolute configuration of cytostatin could be assigned. Key structural elements of cytostatin are an alpha,beta-unsaturated lactone group and a side chain embodying a phosphate and a rather unstable (Z,Z,E)-triene subunit. In addition, the natural product carries six stereocenters. For the construction of the stereocenters reagent-controlled transformations were used in order to ensure maximum stereochemical flexibility. The Evans syn-aldol reaction was chosen to establish the stereochemistry at C-4, C-5, C-9 and C-10; C-6 was introduced by means of the Evans asymmetric alkylation. In all cases the same chiral auxiliary was employed as stereodirecting group. The stereocenter at C-11 was established by an asymmetric reduction using CBS-oxazaborolidine. Temporary protection of the phosphate group was achieved best by using the base-labile 9-fluorenylmethyl group, which could be cleanly cleaved by an excess of triethylamine; this reaction yielded analytically pure phosphates after a simple aqueous work-up. The (Z,Z,E)-triene embodied in cytostatin was synthesized by means of a Stille coupling as key transformation. The synthesis sequence established in this way readily gave access to a series of analogues with simplified structure. Initial biological testing of these analogues proved that the alpha,beta-unsaturated lactone, the C-11-hydroxy group and a fully deprotected phosphate moiety at C-9 are essential for the PP2A-inhibitory activity of cytostatin. The rather unstable triene moiety in the side chain can be replaced by other lipophilic residues with only moderate decrease of biological activity. Other phosphatases, that is, PP1, VHR, PTP1B, CD45, were not inhibited by cytostatin or any of the analogues, demonstrating the high selectivity of this compound. These findings will be useful for the design and synthesis of cytostatin-derived chemical tools for the study of biological processes influenced by PP2A.

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Section: Biological Evaluation Of Cytostatin Analoguesmentioning

confidence: 99%

Total Synthesis and Biological Evaluation of the Protein Phosphatase 2A Inhibitor Cytostatin and Analogues

Bialy

Waldmann

2004

Chemistry A European J

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“…In addition, DNA damage is also the result of the interference of most DNA-intercalating agents with topoisomerase II (topo II), an enzymatic protein with the role of maintaining the correct topological properties of DNA in cells [7]. Alterations in DNA topoisomerase II has been identified in cell lines selected for resistance to natural product including etoposide and doxorubicin [8,9].…”

Section: Introductionmentioning

confidence: 99%

Studies on the anti-proliferative effects of novel DNA-intercalating bipyridyl–thiourea–Pt(II) complexes against cisplatin-sensitive and -resistant human ovarian cancer cells

Marverti

Cusumano

Ligabue

et al. 2008

Journal of Inorganic Biochemistry

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“…Fostriecin, a novel antitumour antibiotic isolated from Streptomyces pulveraceus (subspecies fostreus ) [8, 9]has antineoplastic activity on a wide spectrum of tumour cells in vitro and against L1210 and P388 murine leukaemias in vivo [10, 11]. Currently, fostriecin is being evaluated as an anticancer drug in human clinical trials [12]. Early studies showed that a possible target of fostriecin was topoisomerase II which is inhibited with an IC 50 of 40 μM [13].…”

Section: Introductionmentioning

confidence: 99%

Purification of protein phosphatase 4 catalytic subunit: inhibition by the antitumour drug fostriecin and other tumour suppressors and promoters

Hastie¹,

Cohen²

1998

FEBS Letters

100

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Protein phosphatase 4 (PP4) is a protein serine/ threonine phosphatase that predominantly localises to centrosomes and plays a role in microtubule organisation at centrosomes. Here, PP4 catalytic subunit has been purified from porcine testis to near homogeneity and a specific activity of 680 mU/mg against phosphorylase a. The antitumour drug, fostriecin, inhibits PP4 catalytic subunit (IC 50 3 nM) with similar potency to PP2A catalytic subunit (IC 50 1.5 nM). PP4 is also inhibited in the nanomolar range by several naturally occurring tumour promoters and toxins, with similar IC 50 values to those obtained for PP2A. The gene for human PP4 catalytic subunit localises to 16p11.2.z 1998 Federation of European Biochemical Societies.

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Fostriecin

Cited by 43 publications

References 0 publications

Total Synthesis and Biological Evaluation of the Protein Phosphatase 2A Inhibitor Cytostatin and Analogues

Total Synthesis and Biological Evaluation of the Protein Phosphatase 2A Inhibitor Cytostatin and Analogues

Studies on the anti-proliferative effects of novel DNA-intercalating bipyridyl–thiourea–Pt(II) complexes against cisplatin-sensitive and -resistant human ovarian cancer cells

Purification of protein phosphatase 4 catalytic subunit: inhibition by the antitumour drug fostriecin and other tumour suppressors and promoters

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