Faculty of Chemistry, Adam Mickiewicz University, Poznan, Poland.
Department of Pharmacology, Poznan University of Medical Sciences, Poznan, Poland.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):1898-1904. doi: 10.1080/14756366.2021.1960829.
Geldanamycin () has been modified by different type neutral/acidic/basic substituents (-) and by quinuclidine motif (), transformed into ammonium salts (-) at C(17). These compounds have been characterised by spectroscopic and x-ray methods. Derivative shows better potency than in MCF-7, MDA-MB-231, A549 and HeLa (ICs = 0.09-1.06 µM). Transformation of into salts - reduces toxicity (by 11-fold) at attractive potency, e.g. MCF-7 cell line (IC∼2 µM). Our studies show that higher water solubility contributes to lower toxicity of salts than in healthy CCD39Lu and HDF cells. The use of mixtures with potentiators PEI and DOX enhanced anticancer effects from IC∼2 µM to IC∼0.5 µM in SKBR-3, SKOV-3, and PC-3 cancer cells, relative to . Docking studies showed that complexes between quinuclidine-bearing - and Hsp90 are stabilised by extra hydrophobic interactions between the C(17)-arms and K58 or Y61 of Hsp90.
格尔德霉素 () 已被不同类型的中性/酸性/碱性取代基 (-) 和奎宁环基 () 修饰，并在 C(17) 处转化为铵盐 (-)。这些化合物已通过光谱和 X 射线方法进行了表征。衍生物 在 MCF-7、MDA-MB-231、A549 和 HeLa 细胞中比 具有更好的活性 (ICs = 0.09-1.06 μM)。 将 转化为盐 - 在保持吸引力的活性（例如 MCF-7 细胞系，IC∼2 μM）的同时降低了毒性（降低了 11 倍）。我们的研究表明，较高的水溶性有助于降低盐的毒性，而不是在健康的 CCD39Lu 和 HDF 细胞中。与 相比，将 与增效剂 PEI 和 DOX 混合使用可增强 SKBR-3、SKOV-3 和 PC-3 癌细胞中从 IC∼2 μM 至 IC∼0.5 μM 的抗癌效果。对接研究表明，带有奎宁环的 - 和 Hsp90 之间的复合物通过 C(17)-臂和 Hsp90 的 K58 或 Y61 之间的额外疏水性相互作用得到稳定。
