Geldanamycin
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MedKoo CAT#: 205922

CAS#: 30562-34-6

Description: Geldanamycin is a benzoquinone ansamycin antibiotic that binds to Hsp90 (Heat Shock Protein 90) and inhibits its function. HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis. Hsp90-geldanamycin complex. PDB 1yet Geldanamycin induces the degradation of proteins that are mutated in tumor cells such as v-Src, Bcr-Abl and p53 preferentially over their normal cellular counterparts. This effect is mediated via HSP90. Despite its potent antitumor potential, geldanamycin presents several major drawbacks as a drug candidate (namely, hepatotoxicity) that have led to the development of geldanamycin analogues.


Chemical Structure

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Geldanamycin
CAS# 30562-34-6

Theoretical Analysis

MedKoo Cat#: 205922
Name: Geldanamycin
CAS#: 30562-34-6
Chemical Formula: C29H40N2O9
Exact Mass: 560.27338
Molecular Weight: 560.6359
Elemental Analysis: C, 62.13; H, 7.19; N, 5.00; O, 25.68

Price and Availability

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50.0mg USD 90.0 Same day
100.0mg USD 150.0 Same day
200.0mg USD 250.0 Same day
500.0mg USD 450.0 Same day
1.0g USD 750.0 Same day
2.0g USD 1350.0 Same day
5.0g USD 2950.0 Same day
10.0g USD 5250.0 2 Weeks
20.0g USD 8850.0 2 Weeks
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Synonym: NSC 122750; NSC-122750; NSC122750; U 29135; U-29135; U29135. Geldanamycin.

IUPAC/Chemical 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

InChi Key: QTQAWLPCGQOSGP-KSRBKZBZSA-N

InChi Code: 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

SMILES Code: NC(O[C@@H](/C(C)=C/[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC1=C2OC)[C@@H](OC)/C=C\C=C(C)\C(NC(C1=O)=CC2=O)=O)=O

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Geldanamycin is a Hsp90 inhibitor with antimicrobial activity against many Gram-positive and some Gram-negative bacteria as well as has anti-influenza virus H5N1 activities.
In vitro activity: To examine the effect of GA (Geldanamycin), an HSP 90 inhibitor, in the expression of HSPs, the expression levels of HSP 70 and HSP 90 were examined. GA resulted in the increased expression of HSP 70 (Fig. 1A). However, the expression level of HSP 90 was not significantly changed with GA, which inhibits the function of HSP 90 by binding to the ADP/ATP-binding pocket of the protein. In order to examine the effect of GA on the viability of 3NP-stimulated striatal cells, the cells were treated with 3NP in the absence or presence of GA. Significant striatal cell death was observed with 3NP treatment in MTT and LDH assays (Fig. 2A and B). However, GA significantly attenuated 3NP-induced striatal cell death. In addition, the number of positive cells of 7-AAD and FITC, which indicate dead cells, was significantly reduced with GA in the FACS analysis (Fig. 2Ca and b). In addition, GA significantly reduced the number of 3NP-induced apoptotic nuclei (Fig. 3B). To investigate the effects of GA in 3NP-induced ROS production, the intracellular ROS generation was measured in the absence or presence of GA in 3NP-challenged striatal cells. Treatment of 3NP resulted in the production of a considerable amount of the intracellular ROS in striatal cells. GA significantly attenuated 3NP-induced ROS production, albeit not completely (Fig. 4). Fig. 4A shows a representative confocal image of intracellular level of ROS and Fig. 4B shows quantitative analysis of ROS production. The result demonstrates that GA protects cells by inhibiting the production of ROS in 3NP-challenged striatal cells. GA may be a valuable therapeutic agent to increase the intracellular level of HSP 70, which plays a beneficial role in the pathogenesis of HD (Huntington’s disease). Int J Mol Med. 2014 Jul; 34(1): 24–34. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4072345/
In vivo activity: The in vivo anti-HSV-2 activity of GA was evaluated in the mouse HSV-2 vagina model. In mouse HSV-2 vaginal model, symptoms of illness that were observed in mice after vaginal HSV-2 infection include: puff fur, arched backs, feeble gait, hind limb paralysis, wet fur that was stained by feces in the anus vaginal region, swollen red vulva, hair loss and skin lesions in the anus vaginal region and on the hind limbs, and death. Administration of GA suspension to vagina after HSV-2 infection (1.43, 2.86 and 5.72 mg kg−1, t.i.d. for 7 days) protected the infected mice from death, and increased the average survival days in a dose-dependent manner. The differences were statistically significant when compared with untreated infected controls (Table 2). As shown in Figure 2, GA also significantly reduced the shedding of HSV-2 from mice vagina. Samples of vaginal secretions from all mice in each group were collected individually at 96 h post infection. HSV-2 titers were determined by a cytopathic effect assay. GA 5.72, 2.86 and 1.43 mg kg−1 treatment reduced HSV-2 shedding by 794, 126 and 126 times, as compared with the infected control group, respectively. In summary, GA efficiently inhibits HSV-2 replication in vivo and shows therapeutic effects better than that of ACV. Reference: J Antibiot (Tokyo). 2012; 65(10): 509–512. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094714/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 18.0 32.11

Preparing Stock Solutions

The following data is based on the product molecular weight 560.6359 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Pezzulo AA, Tudas RA, Stewart CG, Buonfiglio LGV, Lindsay BD, Taft PJ, Gansemer ND, Zabner J. HSP90 inhibitor geldanamycin reverts IL-13- and IL-17-induced airway goblet cell metaplasia. J Clin Invest. 2019 Feb 1;129(2):744-758. doi: 10.1172/JCI123524. Epub 2019 Jan 14. PMID: 30640172; PMCID: PMC6355221. 2. Choi YJ, Kim NH, Lim MS, Lee HJ, Kim SS, Chun W. Geldanamycin attenuates 3‑nitropropionic acid‑induced apoptosis and JNK activation through the expression of HSP 70 in striatal cells. Int J Mol Med. 2014 Jul;34(1):24-34. doi: 10.3892/ijmm.2014.1747. Epub 2014 Apr 22. PMID: 24756698; PMCID: PMC4072345. 3. Wang C, Liu P, Luo J, Ding H, Gao Y, Sun L, Luo F, Liu X, He H. Geldanamycin Reduces Acute Respiratory Distress Syndrome and Promotes the Survival of Mice Infected with the Highly Virulent H5N1 Influenza Virus. Front Cell Infect Microbiol. 2017 Jun 15;7:267. doi: 10.3389/fcimb.2017.00267. PMID: 28664154; PMCID: PMC5471324. 4. Li YH, Lu QN, Wang HQ, Tao PZ, Jiang JD. Geldanamycin, a ligand of heat shock protein 90, inhibits herpes simplex virus type 2 replication both in vitro and in vivo. J Antibiot (Tokyo). 2012 Oct;65(10):509-12. doi: 10.1038/ja.2012.67. Epub 2012 Aug 22. PMID: 22909975; PMCID: PMC7094714.
In vitro protocol: 1. Pezzulo AA, Tudas RA, Stewart CG, Buonfiglio LGV, Lindsay BD, Taft PJ, Gansemer ND, Zabner J. HSP90 inhibitor geldanamycin reverts IL-13- and IL-17-induced airway goblet cell metaplasia. J Clin Invest. 2019 Feb 1;129(2):744-758. doi: 10.1172/JCI123524. Epub 2019 Jan 14. PMID: 30640172; PMCID: PMC6355221. 2. Choi YJ, Kim NH, Lim MS, Lee HJ, Kim SS, Chun W. Geldanamycin attenuates 3‑nitropropionic acid‑induced apoptosis and JNK activation through the expression of HSP 70 in striatal cells. Int J Mol Med. 2014 Jul;34(1):24-34. doi: 10.3892/ijmm.2014.1747. Epub 2014 Apr 22. PMID: 24756698; PMCID: PMC4072345.
In vivo protocol: 1. Wang C, Liu P, Luo J, Ding H, Gao Y, Sun L, Luo F, Liu X, He H. Geldanamycin Reduces Acute Respiratory Distress Syndrome and Promotes the Survival of Mice Infected with the Highly Virulent H5N1 Influenza Virus. Front Cell Infect Microbiol. 2017 Jun 15;7:267. doi: 10.3389/fcimb.2017.00267. PMID: 28664154; PMCID: PMC5471324. 4. Li YH, Lu QN, Wang HQ, Tao PZ, Jiang JD. Geldanamycin, a ligand of heat shock protein 90, inhibits herpes simplex virus type 2 replication both in vitro and in vivo. J Antibiot (Tokyo). 2012 Oct;65(10):509-12. doi: 10.1038/ja.2012.67. Epub 2012 Aug 22. PMID: 22909975; PMCID: PMC7094714.

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1: Gorska M, Popowska U, Sielicka-Dudzin A, Kuban-Jankowska A, Sawczuk W, Knap N, Cicero G, Wozniak F. Geldanamycin and its derivatives as Hsp90 inhibitors. Front Biosci. 2012 Jun 1;17:2269-77. Review. PubMed PMID: 22652777.

2: Fukuyo Y, Hunt CR, Horikoshi N. Geldanamycin and its anti-cancer activities. Cancer Lett. 2010 Apr 1;290(1):24-35. Epub 2009 Oct 21. Review. PubMed PMID: 19850405.

3: Hadden MK, Lubbers DJ, Blagg BS. Geldanamycin, radicicol, and chimeric inhibitors of the Hsp90 N-terminal ATP binding site. Curr Top Med Chem. 2006;6(11):1173-82. Review. PubMed PMID: 16842154.

4: Chiosis G, Caldas Lopes E, Solit D. Heat shock protein-90 inhibitors: a chronicle from geldanamycin to today's agents. Curr Opin Investig Drugs. 2006 Jun;7(6):534-41. Review. PubMed PMID: 16784024.

5: Neckers L. Chaperoning oncogenes: Hsp90 as a target of geldanamycin. Handb Exp Pharmacol. 2006;(172):259-77. Review. PubMed PMID: 16610363.

6: Miyata Y. Hsp90 inhibitor geldanamycin and its derivatives as novel cancer chemotherapeutic agents. Curr Pharm Des. 2005;11(9):1131-8. Review. PubMed PMID: 15853661.

7: Sausville EA. Geldanamycin analogs. J Chemother. 2004 Nov;16 Suppl 4:68-9. Review. PubMed PMID: 15688614.

8: Liao ZY, Zhen YS. [Advances in antitumor activity of the hsp90 inhibitor geldanamycin]. Yao Xue Xue Bao. 2001 Sep;36(9):716-20. Review. Chinese. PubMed PMID: 12580116.

9: Blagosklonny MV. Hsp-90-associated oncoproteins: multiple targets of geldanamycin and its analogs. Leukemia. 2002 Apr;16(4):455-62. Review. PubMed PMID: 11960322.

10: Ochel HJ, Eichhorn K, Gademann G. Geldanamycin: the prototype of a class of antitumor drugs targeting the heat shock protein 90 family of molecular chaperones. Cell Stress Chaperones. 2001 Apr;6(2):105-12. Review. Erratum in: Cell Stress Chaperones 2001 Jul;6(3):295. PubMed PMID: 11599571; PubMed Central PMCID: PMC434387.



Additional Information

Geldanamycin was originally discovered in the organism Streptomyces hygroscopicus. It is a macrocyclic polyketide that is synthesized by a Type I polyketide synthase. The genes gelA, gelB, and gelC encode for the polyketide synthase. The PKS is first loaded with 3-amino-5-hydroxybenzoic acid (AHBA). It then utilizes malonyl-CoA, methylmalonyl-CoA, and methoxymalonyl-CoA to synthesize the precursor molecule Progeldanamycin.   This precursor is subjected to several enzymatic and non-enzymatic tailoring steps to produce the active molecule Geldanamycin, which include hydroxylation, o-methylation, carbamoylation, and oxidation.