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

• ChemBase ID: 72537
• Molecular Formular: C31H43N3O8
• Molecular Mass: 585.68842
• Monoisotopic Mass: 585.30501535
• SMILES: C1(=C2C(=O)C(=CC1=O)NC(=O)/C(=C/C=C\[C@@H]([C@H](/C(=C/[C@@H]([C@H]([C@H](C[C@@H](C2)C)OC)O)C)/C)OC(=O)N)OC)/C)NCC=C
• Canonical SMILES: C=CCNC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)/[C@@H]([C@H](/C=C\C=C(\C(=O)NC(=CC1=O)C2=O)/C)OC)OC(=O)N
• InChI: InChI=1S/C31H43N3O8/c1-8-12-33-26-21-13-17(2)14-25(41-7)27(36)19(4)15-20(5)29(42-31(32)39)24(40-6)11-9-10-18(3)30(38)34-22(28(21)37)16-23(26)35/h8-11,15-17,19,24-25,27,29,33,36H,1,12-14H2,2-7H3,(H2,32,39)(H,34,38)/b11-9-,18-10+,20-15+/t17-,19+,24+,25+,27-,29+/m1/s1
• InChIKey: AYUNIORJHRXIBJ-TXHRRWQRSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (8S,9S,12S,13R,14S,16R)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-19-[(prop-2-en-1-yl)amino]-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl carbamate; (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-19-[(prop-2-en-1-yl)amino]-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl carbamate
• IUPAC Traditional name: (8S,9S,12S,13R,14S,16R)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-19-(prop-2-en-1-ylamino)-2-azabicyclo[16.3.1]docosa-1(21),4,6,10,18-pentaen-9-yl carbamate; tanespimycin
• Synonyms: 17-N-Allylamino-17-demethoxygeldanamycin; 17-(Allylamino)geldanamycin; 17-Demethoxy-17-allylamino geldanamycin; 17-AAG; CP 127374; Geldanamycin,17-demethoxy-17-(2-propenylamino)-; NSC 330507; 17-(Allylamino)-17-demethoxygeldanamycin; Tanespimycin; Geldanamycin; NSC330507; 17-AAG(Geldanamycin)

Database IDs

• CAS Number: 75747-14-7
• MDL Number: MFCD04973892
• PubChem SID: 162037462
• PubChem CID: 6440175; 6505803
• CHEMBL: 109480
• Chemspider ID: 21106220
• Wikipedia Title: 17-N-Allylamino-17-demethoxygeldanamycin

CALCULATED PROPERTIES

• Acid pKa: 12.775146
• H Acceptors: 8
• H Donor: 4
• LogD (pH = 5.5): 2.5650165
• LogD (pH = 7.4): 2.565015
• Log P: 2.5650165
• Molar Refractivity: 163.5229 cm^3
• Polarizability: 61.361977 Å^3
• Polar Surface Area: 166.28 Å^2
• Rotatable Bonds: 7
• Lipinski's Rule of Five: false

PROPERTIES

Physical Property

• Solubility: DMSO; DMSO: soluble; methanol: soluble
• Apperance: solid

Safety Information

• Storage Condition: -20°C
• German water hazard class: 3
• Personal Protective Equipment: Eyeshields, Gloves, type N95 (US), type P1 (EN143) respirator filter
• Storage Temperature: -20°C

Pharmacology Properties

• Target: HSP

Product Information

• Purity: ≥98% (HPLC)
• Salt Data: Free Base
• Shipped in: wet ice
• Empirical Formula (Hill Notation): C31H43N3O8

DETAILS

Selleck Chemicals - S1141

Research Area

• Description: Solid tumours,Multiple myeloma,cancer

Biological Activity

• Description: 17-AAG (Tanespimycin) is a potent HSP90 inhibitor with IC50of 5 nM.
• Targets: HSP90
• IC50: 5 nM ^[1]
• In Vitro: 17-AAG, an analog of geldanamycin, exhibits greater than 100 times higher binding affinity for Hsp90 derived from HER-2-overexpressing cancer cells (BT474, N87, SKOV3 and SKBR3) or BT474 breast carcinoma cells with IC50 values of 5-6 nM. ^[1] 17-AAG causes the degradation of HER2, HER3, Akt, and both mutant and wild-type androgen receptor (AR), leading to the RB-dependent G1 growth arrest of prostate cancer cells such as LNCaP, LAPC-4, DU-145, and PC-3 with IC50 values of 25-45 nM. ^[2] In addition to inducing apoptosis of Ba/F3 cells transformed with wild-type BCR-ABL with an IC50 of 5.2 μM, 17-AAG has the ability to induce apoptosis of cells transformed with imatinib mesylate-resistant T315I and E255K BCR-ABL mutants with IC50 values of 2.3 μM and 1.0 μM, respectively, by inducing the degradation of both wild-type BCR-ABL protein and mutants. ^[3]
• In Vivo: 17-AAG displays significantly higher binding affinity for Hsp90 from 3T3-src, B16 or CT26 xenografts in nude mice with IC50 values of 8-35 nM as compared with that from the normal tissues with IC50 values of 200-600 nM. ^[1] Administration of 17-AAG (~50 mg/kg) causes significant decline in AR, HER2, HER3, and Akt expression in a dose-dependent manner with >50% decline at dose of 50 mg/kg, resulting in the dose-dependent inhibition of androgen-dependent (CWR22) and –independent (CWR22R and CWRSA6) prostate cancer xenografts growth by 67%, 80% and 68% at dose of 50 mg/kg, respectively. ^[2]
• Clinical Trials: A Phase II study of 17-AAG in patients with relapsed/refractory CD30 plus anaplastic large cell lymphoma (ALCL) relapsed/refractory mantle cell lymphoma (MCL) and relapsed/refractory classical Hodgkin's lymphoma (HL) has been completed.
• Features: 17-AAG displays significantly low toxicity toward normal cells.

Protocol

• Protocol: Kinase Assay ^[1]
• Hsp90 binding assays: Purified native Hsp90 protein or cell lysates from HER-2-overexpressing cancer cells (BT474, N87, SKOV3 and SKBR3) or BT474 breast carcinoma cells in lysis buffer (20 mM HEPES, pH 7.3, 1 mM EDTA, 5 mM MgCl₂, 100 mM KCl) are incubated with various concentrations of 17-AAG for 30 minutes at 4 °C, and then incubated with biotin-GM linked to BioMag streptavidin magnetic beads for 1 hour at 4 °C. Tubes are placed on a magnetic rack, and the unbound supernatant removed. The magnetic beads are washed three times in lysis buffer and heated for 5 minutes at 95 °C in SDS–PAGE sample buffer. Samples are analysed on SDS protein gels, and western blots done using indicated antibodies. Bands in the western blots are quantified using the Bio-rad Fluor-S MultiImager, and the percentage inhibition of binding of Hsp90 to the biotin-GMwas calculated. The IC50 reported is the concentration of 17-AAG needed to cause half-maximal inhibition of binding.
• Protocol: Cell Assay ^[1]
• Cell Lines: BT474, SKBR3, N87, SKOV3, MCF7, MDA468, Hs578T, Hs578Bst, A549, HT29, U87, SKMG3, HT1080, RPTEC, NDF, HMVEC, HMEC, HUVEC, and PBMC cells
• Concentrations: Dissolved in DMSO, final concentrations ~10 μM
• Incubation Time: 5 days
• Methods: Cells are seeded in 96-well plates at 2,000 cells per well in a final culture volume of 100 μL for 24 hours before the addition of increasing concentrations of 17-AAG that is incubated for 5 days. Viable cell number is determined using the Celltiter 96 AQueous Nonradioactive Cell Proliferation Assay. The value of the background absorbance at 490 nm (A₄₉₀) of wells not containing cells is subtracted. Percentage of viable cells = (A₄₉₀ of 17-AAG treated sample/A₄₉₀ untreated cells) × 100. The IC50 is defined as the concentration that gave rise to 50% viable cell number.
• Protocol: Animal Study ^[2]
• Animal Models: Male nu/nu athymic mice inoculated s.c. with androgen-dependent CWR22 xenograft, and female nu/nu athymic mice inoculated s.c. with androgen-independent xenografts CWR22R and CWRSA6
• Formulation: Dissolved in DMSO, and diluted in egg phospholipids (EPL) vehicle
• Doses: ~50 mg/kg
• Administration: Injection i.p.

References

• References: [1] Kamal A, et al. Nature, 2003, 425(6956), 407-410.
• References: [2] Solit DB, et al. Clin Cancer Res, 2002, 8(5), 986-993.
• References: [3] Gorre ME, et al. Blood, 2002, 100(8), 3041-3044.

Sigma Aldrich - A8476

Biochem/physiol Actions
Potent inhibitor of heat shock protein 90 (Hsp90). 17-AAG is a less toxic analog than geldanamycin. It induces apoptosis and displays antitumor effects. 17-AAG inhibits the activity of oncogenic proteins such as N-ras, Ki-ras, c-Akt, and p185erB2.
Application
17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) inhibits heat shock protein 90 (Hsp90), the expression of heat shock factor-1, and the activity of oncogenic proteins such as N-ras, Ki-ras, c-Akt, and p185erB2. In addition to its anti-tumor effects, 17-AAG also induces apoptosis.

REFERENCES

• Kamal A, et al. Nature, 2003, 425(6956), 407-410.
• Solit DB, et al. Clin Cancer Res, 2002, 8(5), 986-993.
• Gorre ME, et al. Blood, 2002, 100(8), 3041-3044.