geldanamycin (CHEBI:5292)

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CHEBI:5292 - geldanamycin

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ChEBI Name	geldanamycin

ChEBI ID	CHEBI:5292

Definition	An ansamycin consisting of a 19-membered macrocyle incorporating a benzoquinone ring and a lactam functionality. It shows antimicrobial activity against many Gram-positive and some Gram-negative bacteria.

Stars	This entity has been manually annotated by the ChEBI Team.

Secondary ChEBI IDs	CHEBI:42670

Supplier Information	ChemicalBook:CB8462842, eMolecules:30154536, eMolecules:1934769, eMolecules:36500472, ZINC000100064834

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Molfile

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M END): 25 ms

reading 80 atoms

ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false

1 model in this collection. Use getProperty "modelInfo" or getProperty "auxiliaryInfo" to inspect them.

Default Van der Waals type for model set to Babel

80 atoms created

ModelSet: not autobonding; use forceAutobond=true to force automatic bond creation

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Molfile expand

Wikipedia	License
Geldanamycin is a 1,4-benzoquinone ansamycin antitumor antibiotic that inhibits the function of Hsp90 (Heat Shock Protein 90) by binding to the unusual ADP/ATP-binding pocket of the protein. HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis. Geldanamycin induces the degradation of proteins that are mutated or overexpressed in tumor cells such as v-Src, Bcr-Abl, p53, and ERBB2. This effect is mediated via HSP90. Despite its potent antitumor potential, geldanamycin presents several major drawbacks as a drug candidate such as hepatotoxicity, further, Jilani et al.. reported that geldanamycin induces the apoptosis of erythrocytes under physiological concentrations. These side effects have led to the development of geldanamycin analogues, in particular analogues containing a derivatisation at the 17 position: 17-AAG 17-DMAG
Read full article at Wikipedia

Formula

C29H40N2O9

Net Charge

Average Mass

560.63590

Monoisotopic Mass

560.27338

InChI

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

InChIKey

QTQAWLPCGQOSGP-KSRBKZBZSA-N

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

Roles Classification
Biological Role(s):	antiviral agent A substance that destroys or inhibits replication of viruses. antimicrobial agent A substance that kills or slows the growth of microorganisms, including bacteria, viruses, fungi and protozoans. cysteine protease inhibitor Any protease inhibitor that restricts the action of a cysteine protease. Hsp90 inhibitor An EC 3.6.4.10 (non-chaperonin molecular chaperone ATPase) inhibitor that blocks the action of heat shock protein 90.

Application(s):	antineoplastic agent A substance that inhibits or prevents the proliferation of neoplasms.

View more via ChEBI Ontology

ChEBI Ontology
Outgoing	geldanamycin (CHEBI:5292) has role antimicrobial agent (CHEBI:33281) geldanamycin (CHEBI:5292) has role antineoplastic agent (CHEBI:35610) geldanamycin (CHEBI:5292) has role antiviral agent (CHEBI:22587) geldanamycin (CHEBI:5292) has role cysteine protease inhibitor (CHEBI:64152) geldanamycin (CHEBI:5292) has role Hsp90 inhibitor (CHEBI:63962) geldanamycin (CHEBI:5292) is a 1,4-benzoquinones (CHEBI:132124) geldanamycin (CHEBI:5292) is a ansamycin (CHEBI:22565) geldanamycin (CHEBI:5292) is a carbamate ester (CHEBI:23003) geldanamycin (CHEBI:5292) is a organic heterobicyclic compound (CHEBI:27171)

Incoming	alvespimycin (CHEBI:65324) has functional parent geldanamycin (CHEBI:5292) retaspimycin (CHEBI:71975) has functional parent geldanamycin (CHEBI:5292) tanespimycin (CHEBI:64153) has functional parent geldanamycin (CHEBI:5292)

IUPAC Name

(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl carbamate

Synonyms	Sources
GELDANAMYCIN	PDBeChem
Geldanamycin	KEGG COMPOUND

Manual Xrefs	Databases
C00018795	KNApSAcK
C11222	KEGG COMPOUND
GDM	PDBeChem
Geldanamycin	Wikipedia
View more database links

Registry Numbers	Types	Sources
14205884	Reaxys Registry Number	Reaxys
30562-34-6	CAS Registry Number	ChemIDplus

Citations

McNamara AV, Barclay M, Watson AJ, Jenkins JR (2012)
Hsp90 inhibitors sensitise human colon cancer cells to topoisomerase I poisons by depletion of key anti-apoptotic and cell cycle checkpoint proteins.
Biochemical pharmacology 83, 355-367 [PubMed:22138446]
[show Abstract]

Haupt A, Joberty G, Bantscheff M, Fröhlich H, Stehr H, Schweiger MR, Fischer A, Kerick M, Boerno ST, Dahl A, Lappe M, Lehrach H, Gonzalez C, Drewes G, Lange BM (2012)
Hsp90 inhibition differentially destabilises MAP kinase and TGF-beta signalling components in cancer cells revealed by kinase-targeted chemoproteomics.
BMC cancer 12, 38 [PubMed:22277058]
[show Abstract]

Neckers L, Workman P (2012)
Hsp90 molecular chaperone inhibitors: are we there yet?
Clinical cancer research : an official journal of the American Association for Cancer Research 18, 64-76 [PubMed:22215907]
[show Abstract]

Sultana R, Theodoraki MA, Caplan AJ (2012)
UBR1 promotes protein kinase quality control and sensitizes cells to Hsp90 inhibition.
Experimental cell research 318, 53-60 [PubMed:21983172]
[show Abstract]

Chen WW, Yu H, Fan HB, Zhang CC, Zhang M, Zhang C, Cheng Y, Kong J, Liu CF, Geng D, Xu X (2012)
RIP1 mediates the protection of geldanamycin on neuronal injury induced by oxygen-glucose deprivation combined with zVAD in primary cortical neurons.
Journal of neurochemistry 120, 70-77 [PubMed:21985437]
[show Abstract]

Eichner S, Eichner T, Floss HG, Fohrer J, Hofer E, Sasse F, Zeilinger C, Kirschning A (2012)
Broad substrate specificity of the amide synthase in S. hygroscopicus--new 20-membered macrolactones derived from geldanamycin.
Journal of the American Chemical Society 134, 1673-1679 [PubMed:22136518]
[show Abstract]

Mout R, Xu ZD, Wolf AK, Jo Davisson V, Jarori GK (2012)
Anti-malarial activity of geldanamycin derivatives in mice infected with Plasmodium yoelii.
Malaria journal 11, 54 [PubMed:22361388]
[show Abstract]

Background

Geldanamycin (GA), a benzoquinone ansamycin antibiotic has been shown in vitro to possess anti-plasmodial activity. Pharmacological activity of this drug is attributed to its ability to inhibit PfHSP90. The parasite growth arrest has been shown to be due to drug-induced blockage of the transition from ring to trophozoite stage. To further evaluate the consequences of this pharmacodynamic feature, the anti-malarial activity of GA analogs with enhanced drug properties in a Plasmodium-infected animal model have been evaluated for their capacity to induce clearance of the parasite. In the process, a hypothesis was subsequently tested regarding the susceptibility of the cured animals to malaria reflected in an attenuated parasite load that may be evoked by a protective immune response in the host.

Methods

Six weeks old Swiss mice were infected with a lethal Plasmodium yoelii (17XL) strain. On appearance of clinical symptoms of malaria, these animals were treated with two different GA derivatives and the parasite load was monitored over 15-16 days. Drug-treated animals cured of the parasite were then re-challenged with a lethal dose of P. yoelii 17XL. Serum samples from GA cured mice that were re-challenged with P. yoelii 17XL were examined for the presence of antibodies against the parasite proteins using western blot analysis.

Results

Treatment of P. yoelii 17XL infected mice with GA derivatives showed slow recovery from clinical symptoms of the disease. Blood smears from drug treated mice indicated a dominance of ring stage parasites when compared to controls. Although, P. yoelii preferentially invades normocytes (mature rbcs), in drug-treated animals there was an increased invasion of reticulocytes. Cured animals exhibited robust protection against subsequent infection and serum samples from these animals showed antibodies against a vast majority of parasite proteins.

Conclusions

Treatment with GA derivatives blocked the transition from ring to trophozoite stage presumably by the inhibition of HSP90 associated functions. Persistence of parasite in ring stage leads to robust humoral immune response as well as a shift in invasion specificity from normocytes to reticulocyte. It is likely that the treatment with the water-soluble GA derivative creates an attenuated state (less virulent with altered invasion specificity) that persists in the host system, allowing it to mount a robust immune response.

Wu X, Tao P, Nie H (2011)
Geldanamycin is effective in the treatment of herpes simplex virus epithelial keratitis in a rabbit model.
Clinical & experimental ophthalmology 39, 779-783 [PubMed:22050565]
[show Abstract]

Last Modified

02 June 2016

CHEBI:5292 - geldanamycin

Background

Methods

Results

Conclusions

Background

Methods

Results

Conclusions

Background

Methods

Results

Conclusion

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