- Synthesis and biological activities of novel 17-aminogeldanamycin derivatives
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A library of over sixty 17-alkylamino-17-demethoxygeldanamycin were synthesized. Their affinity for Hsp90, ability to inhibit growth of SKBr3 mammalian cells, and in selected cases, water solubility, were measured. The structure-activity relationships of binding affinity to Hsp90 and cytotoxicity in SKBr3 cells are discussed. Geldanamycin interferes with the action of heat shock protein 90 (Hsp90) by binding to the N-terminal ATP binding site and inhibiting an essential ATPase activity. In a program directed toward finding potent, water soluble inhibitors of Hsp90, we prepared a library of over sixty 17-alkylamino-17-demethoxygeldanamycin analogs, and compared their affinity for Hsp90, ability to inhibit growth of SKBr3 mammalian cells, and in selected cases, water solubility. Over 20 analogs showed cell growth inhibition potencies similar to that of 17-allylamino-17-demethoxygeldanamycin (17-AAG), the front-runner geldanamycin analog that is currently in multiple clinical trials. Many of these analogs showed water solubility properties that were desirable for formulation. One of the most potent and water-soluble analogs in the series was 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin (17-DMAG), which was independently prepared by the NCI and will soon enter clinical trials. Importantly, the binding affinity of these analogs to the molecular target Hsp90 does not correlate well with their cytotoxicity in SKBr3 cells.
- Tian, Zong-Qiang,Liu, Yaoquan,Zhang, Dan,Wang, Zhan,Dong, Steven D.,Carreras, Christopher W.,Zhou, Yiqing,Rastelli, Giulio,Santi, Daniel V.,Myles, David C.
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- GELDANAMYCIN AND DERIVATIVES INHIBIT CANCER INVASION AND IDENTIFY NOVEL TARGETS
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Geldanamycin derivatives that block the uPA-plasmin network and inhibit growth and invasion by glioblastoma cells and other tumors at femtomolar concentrations are potentially highly active anti-cancer drugs. GA and various 17-amino-17-demethoxygelddanamycin derivatives are disclosed that block HGF/SF-mediated Met tyrosine kinase receptor-dependent uPA activation at fM levels. Other ansamycins (macbecins I and II), GA derivatives, and radicicol required concentrations several logs higher (≥nM) to achieve such inhibition. The inhibitory activity of tested compounds was discordant with the known ability of drugs of this class to bind to hsp90, indicating the existence of a novel target(s) for HGF/SF -mediated events in tumor development. Methods of using such compounds to inhibit cancer cell activities and to treat tumors are disclosed. Such treatment with low doses of these highly active compounds provide an option for treating various Met-expressing tumors, in particular invasive brain cancers, either alone or in combination with conventional surgery, chemotherapy, or radiotherapy.
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Page/Page column 34
(2008/06/13)
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- Structure-based design of 7-carbamate analogs of geldanamycin
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The 7-carbamate groups of geldanamycin and its 17-(2-dimethylaminoethyl) amino-17-demethoxy derivative (17-DMAG) bind the N-terminal domain of Hsp90 by establishing a network of hydrogen bonds which involve four buried water molecules. In this study, a structure-based approach was used to investigate the effects of displacing some of these waters by modification of the 7-carbamate. A general loss of binding to human Hsp90 was observed, except for replacement of the carbamate with a hydroxamate group which gave an analog with weak activity. Modeling of Hsp90-ligand interactions suggested that the hydroxamate was not able to displace the buried water molecules, while bulkier substituents able to do so proved inactive.
- Rastelli, Giulio,Tian, Zong-Qiang,Wang, Zhan,Myles, David,Liu, Yaoquan
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p. 5016 - 5021
(2007/10/03)
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- Geldanamycin compounds and method of use
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Geldanamycin compounds having a structure according to formula I where Q1, L, L1, R5, R6, and R11 are as defined herein, are useful for treating a disease or disorder ameliorated by inhibiting the function of extracellular heat shock protein-90.
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Page/Page column 11; 12
(2008/06/13)
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