Potent Cytotoxic C-11 Modified Geldanamycin Analogues

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...

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Bibliographic Details
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm900098v