Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
Org Biomol Chem. 2016 Jan 14;14(2):711-715. doi: 10.1039/c5ob02020d.
Frequently present in pancreatic, colorectal and non-small cell lung carcinomas, oncogenic mutant K-Ras must be localised to the plasma membrane (PM) to be functional. Inhibitors of K-Ras PM localisation are therefore putative cancer chemotherapeutics. By screening a microbial extract library in a high content cell-based assay we detected the rare oligomycin class of Streptomyces polyketides as inhibitors of K-Ras PM localisation. Cultivation and fractionation of three unique oligomycin producing Streptomyces strains yielded oligomycins A-E (1-5) and 21-hydroxy-oligomycin A (6), together with the new 21-hydroxy-oligomycin C (7) and 40-hydroxy-oligomycin B (8). Structures for 1-8 were assigned by detailed spectroscopic analysis. Cancer cell viability screening confirmed 1-8 were cytotoxic to human colorectal carcinoma cells (IC50 > 3 μM), and were inhibitors of the ABC transporter efflux pump P-glycoprotein (P-gp), with 5 being comparable in potency to the positive control verapamil. Significantly, oligomycins 1-8 proved to be exceptionally potent inhibitors of K-Ras PM localisation (Emax 0.67-0.75 with an IC50 ~ 1.5-14 nM).
经常存在于胰腺、结直肠和非小细胞肺癌中，致癌突变体 K-Ras 必须定位于质膜（PM）才能发挥功能。因此，K-Ras PM 定位的抑制剂是潜在的癌症化疗药物。通过在高内涵细胞测定中筛选微生物提取物文库，我们检测到罕见的寡霉素类链霉菌聚酮类化合物是 K-Ras PM 定位的抑制剂。对三种独特的产生寡霉素的链霉菌菌株进行培养和分离，得到了寡霉素 A-E（1-5）和 21-羟基寡霉素 A（6），以及新的 21-羟基寡霉素 C（7）和 40-羟基寡霉素 B（8）。通过详细的光谱分析确定了 1-8 的结构。癌细胞活力筛选证实 1-8 对人结直肠癌细胞具有细胞毒性（IC50>3 μM），并且是 ABC 转运蛋白外排泵 P-糖蛋白（P-gp）的抑制剂，其中 5 的效力与阳性对照维拉帕米相当。值得注意的是，寡霉素 1-8 被证明是异常有效的 K-Ras PM 定位抑制剂（Emax 0.67-0.75，IC50~1.5-14 nM）。
