Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C29H40N2O9 |
| Molecular Weight | 560.6359 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 6 / 6 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CO[C@H]1C[C@H](C)CC2=C(OC)C(=O)C=C(NC(=O)\C(C)=C\C=C[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@H]1O)C2=O
InChI
InChIKey=QTQAWLPCGQOSGP-KSRBKZBZSA-N
InChI=1S/C29H40N2O9/c1-15-11-19-25(34)20(14-21(32)27(19)39-7)31-28(35)16(2)9-8-10-22(37-5)26(40-29(30)36)18(4)13-17(3)24(33)23(12-15)38-6/h8-10,13-15,17,22-24,26,33H,11-12H2,1-7H3,(H2,30,36)(H,31,35)/b10-8-,16-9+,18-13+/t15-,17+,22+,23+,24-,26+/m1/s1
Geldanamycin, an antimicrobial compound, was purified in 1970 from the culture filtrates of Streptomyces hygroscopicus var. geldanus var. nova. Geldanamycin is moderately active in vitro against protozoa, bacteria, and fungi. It also has an antineoplastic effect against some cancer cells growing in culture. Molecular studies revealed the binding of geldanamycin to members of the heat shock protein 90 (HSP90) family of molecular chaperones. Interference with the function of these HSPs seems to be the major mechanism of action of geldanamycin.
CNS Activity
Originator
Approval Year
PubMed
| Title | Date | PubMed |
|---|---|---|
| Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. | 2016-01 |
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| The quinone methide aurin is a heat shock response inducer that causes proteotoxic stress and Noxa-dependent apoptosis in malignant melanoma cells. | 2015-01-16 |
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| N-acetylcysteine prevents the geldanamycin cytotoxicity by forming geldanamycin-N-acetylcysteine adduct. | 2014-09-05 |
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| Potential role of HSP90 in mediating the interactions between estrogen receptor (ER) and aryl hydrocarbon receptor (AhR) signaling pathways. | 2014-04-07 |
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| Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. | 2013-12 |
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| Protein-selective capture to analyze electrophile adduction of hsp90 by 4-hydroxynonenal. | 2011-08-15 |
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| Inhibition of HSP90-dependent telomerase activity in amyloid β-induced apoptosis of cerebral endothelial cells. | 2011-08 |
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| Pharmacogenomic approach reveals a role for the x(c)- cystine/glutamate antiporter in growth and celastrol resistance of glioma cell lines. | 2010-03 |
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| Geldanamycin induces production of heat shock protein 70 and partially attenuates ototoxicity caused by gentamicin in the organ of Corti explants. | 2009-09-02 |
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| Enhanced clonogenic survival induced by protein tyrosine phosphatase (PTP) inhibition after Cr(VI) exposure is mediated by c-Raf and Ras activity. | 2009-05 |
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| Proteasome-dependent pharmacological rescue of cystic fibrosis transmembrane conductance regulator revealed by mutation of glycine 622. | 2008-04 |
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| [Geldanamycin inhibits proliferation and motility of human HER2/neu-overexpressing breast cancer cell line SKBr3]. | 2007-10 |
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| Resistance to geldanamycin-induced apoptosis in differentiated neuroblastoma SH-SY5Y cells. | 2007-03-06 |
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| Enhancement of adenoviral MDA-7-mediated cell killing in human lung cancer cells by geldanamycin and its 17-allyl- amino-17-demethoxy analogue. | 2007-01 |
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| The bioreduction of a series of benzoquinone ansamycins by NAD(P)H:quinone oxidoreductase 1 to more potent heat shock protein 90 inhibitors, the hydroquinone ansamycins. | 2006-10 |
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| Pharmacological induction of Hsp70 protects apoptosis-prone cells from doxorubicin: comparison with caspase-inhibitor- and cycle-arrest-mediated cytoprotection. | 2006-09 |
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| Effects of geldanamycin on HIF-1alpha mediated angiogenesis and invasion in prostate cancer cells. | 2006 |
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| Effects of organochlorine insecticides on MAP kinase pathways in human HaCaT keratinocytes: key role of reactive oxygen species. | 2005-08 |
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| Apoptosis induction by a novel retinoid-related molecule requires nuclear factor-kappaB activation. | 2005-06-01 |
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| Interleukin-1beta attenuates beta-very low-density lipoprotein uptake and its receptor expression in vascular smooth muscle cells. | 2005-04 |
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| Predominant Bcl-XL knockdown disables antiapoptotic mechanisms: tumor necrosis factor-related apoptosis-inducing ligand-based triple chemotherapy overcomes chemoresistance in pancreatic cancer cells in vitro. | 2005-03-15 |
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| 15-Hydroxyprostaglandin dehydrogenase can be induced by dexamethasone and other glucocorticoids at the therapeutic level in A549 human lung adenocarcinoma cells. | 2005-03-01 |
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| Src tyrosine kinase regulates CYP17 expression and androstenedione secretion in theca-enriched mouse ovarian cells. | 2004-11 |
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| Autocrine extracellular signal-regulated kinase (ERK) activation in normal human keratinocytes: metalloproteinase-mediated release of amphiregulin triggers signaling from ErbB1 to ERK. | 2004-09 |
|
| Simultaneous inhibition of hsp 90 and the proteasome promotes protein ubiquitination, causes endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity. | 2004-05 |
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| PI3K/Akt is required for heat shock proteins to protect hypoxia-inducible factor 1alpha from pVHL-independent degradation. | 2004-04-02 |
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| Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs. | 2004-03-01 |
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| Hair growth induction by the Tellurium immunomodulator AS101: association with delayed terminal differentiation of follicular keratinocytes and ras-dependent up-regulation of KGF expression. | 2004-02 |
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| Interaction of the PAS B domain with HSP90 accelerates hypoxia-inducible factor-1alpha stabilization. | 2004 |
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| Geldanamycin inhibits migration of glioma cells in vitro: a potential role for hypoxia-inducible factor (HIF-1alpha) in glioma cell invasion. | 2003-08 |
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| Role of the cytosolic chaperones Hsp70 and Hsp90 in maturation of the cardiac potassium channel HERG. | 2003-06-27 |
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| PTHrP [67-86] regulates the expression of stress proteins in breast cancer cells inducing modifications in urokinase-plasminogen activator and MMP-1 expression. | 2003-06-15 |
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| Functional analysis of murine aryl hydrocarbon (AH) receptors defective in nuclear import: impact on AH receptor degradation and gene regulation. | 2003-03 |
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| Geldanamycin inhibits the production of inflammatory cytokines in activated macrophages by reducing the stability and translation of cytokine transcripts. | 2003-02 |
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| ATPase inhibitors suppress actinomycin D-induced apoptosis in leukemia cells. | 2003-01-18 |
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| Ligand-dependent and independent modulation of aryl hydrocarbon receptor localization, degradation, and gene regulation. | 2002-10 |
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| Involvement of human heat shock protein 90 alpha in nicotine-induced apoptosis. | 2002-07-01 |
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| Geldanamycin induces degradation of hypoxia-inducible factor 1alpha protein via the proteosome pathway in prostate cancer cells. | 2002-05-01 |
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| Suppressive effects of ansamycins on inducible nitric oxide synthase expression and the development of experimental autoimmune encephalomyelitis. | 2002-02-15 |
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| Geldanamycin inhibits NF-kappaB activation and interleukin-8 gene expression in cultured human respiratory epithelium. | 2001-07 |
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| Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease. | 2001-06-01 |
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| Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. | 2001-02-02 |
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| Regulation of prostaglandin endoperoxide H synthase-2 induction by dioxin in rat hepatocytes: possible c-Src-mediated pathway. | 2000-12 |
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| Geldanamycin induces heat shock protein expression through activation of HSF1 in K562 erythroleukemic cells. | 1999-10 |
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| 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-mediated membrane translocation of c-Src protein kinase in liver WB-F344 cells. | 1999-07-13 |
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| Alterations in the growth factor signal transduction pathways and modulators of the cell cycle in endocervical cells from macaques exposed to TCDD. | 1998-08 |
|
| Use of c-Src and c-Fos knockout mice for the studies on the role of c-Src kinase signaling in the expression of toxicity of TCDD. | 1998 |
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| Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway. | 1996-10 |
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| Stable and specific binding of heat shock protein 90 by geldanamycin disrupts glucocorticoid receptor function in intact cells. | 1996-06 |
|
| p185erbB2 binds to GRP94 in vivo. Dissociation of the p185erbB2/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185erbB2. | 1996-03-01 |
Patents
Sample Use Guides
In Vivo Use Guide
Curator's Comment: Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent.
Maximum tolerated doses were approximately 20 mg/kg for the mice and 4 mg/kg for the dog.
Route of Administration:
Intravenous
The mechanism of action of geldanamycin was investigated with murine lymphoblastoma L5178Y cells. The agent inhibited the cell growth at concentrations over 0.01 micrograms/ml. Geldanamycin blocked DNA polymerase alpha more markedly than beta and gamma. The degree of inhibition depended upon concentrations of the enzyme but not upon those of template, suggesting a drug-enzyme interaction. IC50 for DNA polymerase alpha was 10 micrograms/ml and for DNA polymerase beta 100 micrograms/ml at low concentrations of enzyme. The inhibition of DNA polymerase alpha by the antibiotic was non-competitive and Ki was 20 microM.
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C1003
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METABOLITE (PARENT)
METABOLITE (PARENT)
SUBSTANCE RECORD
