Tian Zong-Qiang, Wang Zhan, MacMillan Karen S, Zhou Yiqing, Carreras Christopher W, Mueller Thomas, Myles David C, Liu Yaoquan
Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, California 94545, USA.
J Med Chem. 2009 May 28;52(10):3265-73. doi: 10.1021/jm900098v.
17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits the activity of Hsp90, an important target for treatment of cancers. In an effort to identify analogues of geldanamycin (GDM) with properties superior to those of 17-AAG, we synthesized C-11 modified derivatives of GDM including ethers, esters, carbazates, ketones, and oximes and measured their affinity for Hsp90 and their ability to inhibit growth of human cancer cells. In accordance with crystal structures reported for complexes of GDMs with Hsp90, bulky groups attached to C-11 interfered with Hsp90 binding while smaller groups such as 11-O-methyl allowed Hsp90 binding. In addition, these analogues also showed in vitro cytotoxicity against human cancer cell lines. Esterification of the 11-OH of 17-AAG eliminated Hsp90 binding in vitro. The readily hydrolyzed esters acted as prodrugs during the measurement of cytotoxicity. Thus, during these experiments, the esters were hydrolyzed, releasing 17-AAG. Several 11-O-methyl-17-alkylaminogeldanamycin analogues were identified with improved potency relative to 17-AAG.
17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）可抑制热休克蛋白90（Hsp90）的活性，Hsp90是癌症治疗的一个重要靶点。为了鉴定出性能优于17-AAG的格尔德霉素（GDM）类似物，我们合成了GDM的C-11修饰衍生物，包括醚、酯、氨基甲酸酯、酮和肟，并测定了它们对Hsp90的亲和力以及抑制人癌细胞生长的能力。根据报道的GDM与Hsp90复合物的晶体结构，连接在C-11上的庞大基团会干扰与Hsp90的结合，而较小的基团如11-O-甲基则允许与Hsp90结合。此外，这些类似物对人癌细胞系也显示出体外细胞毒性。17-AAG的11-OH酯化消除了其在体外与Hsp90的结合。在细胞毒性测定过程中，易水解的酯起到了前药的作用。因此，在这些实验中，酯发生水解，释放出17-AAG。已鉴定出几种11-O-甲基-17-烷基氨基格尔德霉素类似物，其效力相对于17-AAG有所提高。
