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Issue 27, 2014
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Rare Streptomyces sp. polyketides as modulators of K-Ras localisation

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Abstract

Chemical investigations of a soil-derived Streptomyces sp. led to the isolation of five new polyketides, (+)-oxanthromicin, (±)-hemi-oxanthromicins A/B, (±)-spiro-oxanthromicin A and oxanthroquinone, and the known alkaloid staurosporine, and the detection of four new metastable analogues, (±)-spiro-oxanthromicins B1/B2/C1/C2. Among the compounds tested, SAR investigations established that the synthetic oxanthroquinone ethyl ester and 3-O-methyl-oxanthroquinone ethyl ester were optimal at mislocalising oncogenic mutant K-Ras from the plasma membrane of intact Madin-Darby canine kidney (MDCK) cells (IC50 4.6 and 1.2 μM), while a sub-EC50 dose of (±)-spiro-oxanthromicin A was optimal at potentiating (750%) the K-Ras inhibitory activity of staurosporine (IC50 60 pM). These studies demonstrate that a rare class of Streptomyces polyketide modulates K-Ras plasma membrane localisation, with implications for the future treatment of K-Ras dependent cancers.

Graphical abstract: Rare Streptomyces sp. polyketides as modulators of K-Ras localisation

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Publication details

The article was received on 09 Apr 2014, accepted on 22 May 2014 and first published on 22 May 2014


Article type: Paper
DOI: 10.1039/C4OB00745J
Author version available: Download Author version (PDF)
Citation: Org. Biomol. Chem., 2014,12, 4872-4878
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    Rare Streptomyces sp. polyketides as modulators of K-Ras localisation

    A. A. Salim, X. Xiao, K. Cho, A. M. Piggott, E. Lacey, J. F. Hancock and R. J. Capon, Org. Biomol. Chem., 2014, 12, 4872
    DOI: 10.1039/C4OB00745J

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