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

Angela A. Salim, Xue Xiao, Kwang-Jin Cho, Andrew M. Piggott, Ernest Lacey, John F. Hancock and Robert J. Capon

Organic and Molecular Chemistry 2014, 12, 4872-4878.

Publication Date: May 22, 2014

https://doi.org/10.1039/C4OB00745J

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.

Available at BioAustralis:

(+)-oxanthromicin

(±)-hemi-oxanthromicins A/B

(±)-spiro-oxanthromicin A

staurosporine