TY - JOUR
T1 - Rare Streptomyces sp. polyketides as modulators of K-Ras localisation
AU - Salim, Angela A.
AU - Xiao, Xue
AU - Cho, Kwang Jin
AU - Piggott, Andrew M.
AU - Lacey, Ernest
AU - Hancock, John F.
AU - Capon, Robert J.
PY - 2014/7/21
Y1 - 2014/7/21
N2 - 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-EC 50 dose of (±)-spiro-oxanthromicin A was optimal at potentiating (750%) the K-Ras inhibitory activity of staurosporine (IC 50 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. This journal is
AB - 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-EC 50 dose of (±)-spiro-oxanthromicin A was optimal at potentiating (750%) the K-Ras inhibitory activity of staurosporine (IC 50 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. This journal is
UR - http://www.scopus.com/inward/record.url?scp=84902844809&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/arc/DP120100183
UR - http://purl.org/au-research/grants/arc/LP120100088
U2 - 10.1039/c4ob00745j
DO - 10.1039/c4ob00745j
M3 - Article
C2 - 24875924
AN - SCOPUS:84902844809
SN - 1477-0520
VL - 12
SP - 4872
EP - 4878
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
IS - 27
ER -