Potent Cytotoxic C-11 Modified Geldanamycin Analogues

• Published in: Journal of medicinal chemistry 2009-05, Vol.52 (10), p.3265-3273
• Main Authors: Tian, Zong-Qiang, Wang, Zhan, MacMillan, Karen S, Zhou, Yiqing, Carreras, Christopher W, Mueller, Thomas, Myles, David C, Liu, Yaoquan
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Benzoquinones - chemistry; Benzoquinones - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Esters; General aspects; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; Lactams, Macrocyclic - chemistry; Lactams, Macrocyclic - pharmacology; Medical sciences; Pharmacology. Drug treatments; Prodrugs - chemistry; Protein Binding; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• 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. Esterfication 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.