Institute of Organic Chemistry, Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany.
Org Biomol Chem. 2019 May 29;17(21):5269-5278. doi: 10.1039/c9ob00892f.
Mutasynthetic supplementation of the AHBA blocked mutant strain of S. hygroscopicus, the geldanamycin producer, with 21 aromatic and heteroaromatic amino acids provided new nonquinoid geldanamycin derivatives. Large scale (5 L) fermentation provided four new derivatives in sufficient quantity for full structural characterisation. Among these, the first thiophene derivative of reblastatin showed strong antiproliferative activity towards several human cancer cell lines. Additionally, inhibitory effects on human heat shock protein Hsp90α and bacterial heat shock protein from H. pylori HpHtpG were observed, revealing strong displacement properties for labelled ATP and demonstrating that the ATP-binding site of Hsps is the target site for the new geldanamycin derivatives.
用 21 种芳香族和杂环族氨基酸对吸水链霉菌 AHBA 阻断突变株进行突变合成补充，该突变株是格尔德霉素的生产者，得到了新型非醌格尔德霉素衍生物。在 5L 规模的发酵中，得到了足够数量的四种新型衍生物，可对其进行充分的结构鉴定。其中，雷帕霉素的第一个噻吩衍生物对多种人类癌细胞系显示出强烈的抗增殖活性。此外，还观察到对人热休克蛋白 Hsp90α 和幽门螺杆菌 HpHtpG 的细菌热休克蛋白的抑制作用，表明对标记的 ATP 具有强烈的置换性质，并证明 Hsps 的 ATP 结合位点是新型格尔德霉素衍生物的靶位。
