Geldanamycin

Structural formula
General
Non-proprietary name	Geldanamycin
other names	(4 E , 6 Z , 8 R , 9 R , 10 E , 12 R , 13 S , 14 R , 16 S ) -9 - [(aminocarbonyl) oxy] -13-hydroxy-8,14,19-trimethoxy- 4,10,12,16-tetramethyl-2-azabicyclo [16.3.1] docosa-4,6,10,18,21-pentaene-3,20,22-trione ( IUPAC )
Molecular formula	C 29 H 40 N 2 O 9
Brief description	yellow to orange solid
External identifiers / databases
CAS number 30562-34-6 PubChem 5288382 ChemSpider 10272739 DrugBank DB02424 Wikidata Q904475
properties
Molar mass	560.64 g · mol -1
solubility	almost insoluble in water soluble in DMSO
safety instructions
GHS labeling of hazardous substances no GHS pictograms H and P phrases H: no H-phrases P: no P-phrases
Toxicological data	2500 mg kg −1 ( LD 50 ,  rat ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Geldanamycin is a biologically active chemical compound , more precisely a benzoquinoid ansamycin , which is produced by the bacterium Streptomyces hygroscopicus . It binds specifically to the heat shock protein HSP90 and changes its function. HSP90 target proteins play important roles in the regulation of the cell cycle , cell growth, cell survival, apoptosis , angiogenesis and oncogenesis . By binding of geldanamycin to HSP90, target proteins such as tyrosine kinases, steroid receptors, transcription factors and cell cycle regulating kinases are broken down. It induces the inactivation, destabilization and ultimately the degradation of HIF-1α.

Geldanamycin preferentially induces the breakdown of proteins that are mutated in cancer cells over normal proteins, such as e.g. B. with v-src, bcr-abl and p53 . This effect is mediated by HSP90. Despite its high anti-tumor potential, Geldanamycin has some disadvantages as a drug candidate, in particular hepatotoxicity, which gave rise to the development of Geldanamycin analogues , especially those whose position 17 is derivatized :

• 17-AAG (Tanespimycin)
• 17-DMAG

further reading

• M. Bedin, AM Gaben u. a .: Geldanamycin, an inhibitor of the chaperone activity of HSP90, induces MAPK-independent cell cycle arrest. In: International Journal of Cancer Volume 109, Number 5, May 2004, pp. 643-652, doi : 10.1002 / ijc.20010 . PMID 14999769 .
• L. Whitesell, EG Mimnaugh et al. a .: Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. In: Proceedings of the National Academy of Sciences of the United States of America . Volume 91, Number 18, August 1994, pp. 8324-8328, PMID 8078881 . PMC 44598 (free full text).

• L. Neckers: Hsp90 inhibitors as novel cancer chemotherapeutic agents. In: Trends in Molecular Medicine . Volume 8, Number 4 Suppl, 2002, pp. S55-S61, PMID 11927289 . (Review).
• NJ Mabjeesh, DE Post u. a .: Geldanamycin induces degradation of hypoxia-inducible factor 1alpha protein via the proteosome pathway in prostate cancer cells. In: Cancer Research . Volume 62, Number 9, May 2002, pp. 2478-2482, PMID 11980636 .
• L. Neckers: Development of small molecule Hsp90 inhibitors: utilizing both forward and reverse chemical genomics for drug identification. In: Current Medicinal Chemistry . Volume 10, Number 9, May 2003, pp. 733-739, PMID 12678776 . (Review).
• EA Sausville: Geldanamycin analogs. In: Journal of Chemotherapy . Volume 16 Suppl 4, November 2004, pp. 68-69, doi : 10.1179 / joc.2004.16.Supplement-1.68 . PMID 15688614 . (Review).
• RC Clevenger, JM Raibel et al. a .: Biotinylated geldanamycin. In: The Journal of organic chemistry. Volume 69, Number 13, June 2004, pp. 4375-4380, doi : 10.1021 / jo049848m . PMID 15202892 .
• R. Mandler, H. Kobayashi et al. a .: Herceptin-geldanamycin immunoconjugates: pharmacokinetics, biodistribution, and enhanced antitumor activity. In: Cancer Research . Volume 64, Number 4, February 2004, pp. 1460-1467, PMID 14973048 .
• ZQ Tian, ​​Y. Liu, et al. a .: Synthesis and biological activities of novel 17-aminogeldanamycin derivatives. In: Bioorganic & Medicinal Chemistry . Volume 12, Number 20, October 2004, pp. 5317-5329, doi : 10.1016 / j.bmc.2004.07.053 . PMID 15388159 .

Provider websites

• Geldanamycin from Biomol
• Geldanamycin from Fermentek
• A complete review on Geldanamycin, 17AAG, and 17DMAG

Individual evidence

1. ↑ ^{a b c d} data sheet Geldanamycin from Streptomyces hygroscopicus at Sigma-Aldrich , accessed on February 9, 2013 ( PDF ).
2. ↑ ^{a b c} data sheet Geldanamycin (PDF) from Carl Roth , accessed on February 9, 2013.

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