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467214-21-7 molecular structure
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(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-{[2-(dimethylamino)ethyl]amino}-13-hydroxy-8,14-dimethoxy-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 hydrochloride

ChemBase ID: 72538
Molecular Formular: C32H49ClN4O8
Molecular Mass: 653.20646
Monoisotopic Mass: 652.32389223
SMILES and InChIs

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)NCCN(C)C.Cl
Canonical SMILES:
CO[C@H]1C[C@H](C)CC2=C(NCCN(C)C)C(=O)C=C(C2=O)NC(=O)/C(=C/C=C\[C@@H]([C@H](/C(=C/[C@@H]([C@H]1O)C)/C)OC(=O)N)OC)/C.Cl
InChI:
InChI=1S/C32H48N4O8.ClH/c1-18-14-22-27(34-12-13-36(5)6)24(37)17-23(29(22)39)35-31(40)19(2)10-9-11-25(42-7)30(44-32(33)41)21(4)16-20(3)28(38)26(15-18)43-8;/h9-11,16-18,20,25-26,28,30,34,38H,12-15H2,1-8H3,(H2,33,41)(H,35,40);1H/b11-9-,19-10+,21-16+;/t18-,20+,25+,26+,28-,30+;/m1./s1
InChIKey:
DFSYBWLNYPEFJK-IHLRWNDRSA-N

Cite this record

CBID:72538 http://www.chembase.cn/molecule-72538.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
(4E,6Z,8S,9S,10E,12S,13R,14S,16R)-19-{[2-(dimethylamino)ethyl]amino}-13-hydroxy-8,14-dimethoxy-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 hydrochloride
IUPAC Traditional name
alvespimycin hydrochloride
Synonyms
Alvespimycin
KOS-1022
NSC 707545
17-DMAG hydrochloride
CAS Number
467214-21-7
PubChem SID
162037463
PubChem CID
9852573

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources
Data Source Data ID Price
Selleck Chemicals
S1142 external link Add to cart Please log in.
Data Source Data ID
PubChem 9852573 external link

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem
Acid pKa 12.775154  H Acceptors
H Donor LogD (pH = 5.5) 0.041767485 
LogD (pH = 7.4) 1.5928986  Log P 1.8524113 
Molar Refractivity 172.3793 cm3 Polarizability 64.97228 Å3
Polar Surface Area 169.52 Å2 Rotatable Bonds
Lipinski's Rule of Five false 

PROPERTIES

PROPERTIES

Physical Property Safety Information Pharmacology Properties Product Information Bioassay(PubChem)
Solubility
DMSO expand Show data source
Storage Condition
-20°C expand Show data source
Target
HSP expand Show data source
Salt Data
Hydrochloride expand Show data source

DETAILS

DETAILS

Selleck Chemicals Selleck Chemicals
Selleck Chemicals - S1142 external link
Research Area
Description Cancer
Biological Activity
Description 17-DMAG (Alvespimycin, KOS-1022, NSC 707545) is a potent HSP90 inhibitor with IC50 of 62 nM.
Targets HSP90
IC50 62 nM [1]
In Vitro 17-DMAG displays ~2 times potency against human Hsp90 than 17-AAG, with IC50 of 62 nM versus 119 nM. In SKBR3 and SKOV3 cells which over-express Hsp90 client protein Her2, 17-DMAG causes down-regulation of Her2 with EC50 of 8 nM and 46 nM, respectively, as well as induction of Hsp70 with EC50 of 4 nM and 14 nM, respectively, leading to significant cytotoxicity with GI50 of 29 nM and 32 nM, respectively, consistent with Hsp90 inhibition. [1] 17-DMAG in combination with vorinostat synergistically induces apoptosis of the cultured MCL cells as well as primary MCL cells, more potently than either agent alone, by markedly attenuating the levels of cyclin D1 and CDK4, as well as of c-Myc, c-RAF and Akt. [3] In contrast to 17-AAG which is only active for IKKβ in chronic lymphocytic leukemia (CLL) cells, 17-DMAG treatment effectively leads to depletion of the Hsp90 client protein, resulting in diminished NF-κB p50/p65 DNA binding, decreased NF-κB target gene transcription, and caspase-dependent apoptosis. By targeting the NF-κB family, 17-DMAG selectively mediates dose- and time-dependent cytotoxicity against CLL cells, but not normal T cells or NK cells important for immune surveillance. [5]
In Vivo 17-DMAG treatment at 5 mg/kg or 25 mg/kg thrice per week significantly reduces tumor growth of TMK-1 xenografts, by significantly reducing vessel area and numbers of proliferating tumor cells in sections. [2] Consistent the inhibition of FAK signaling in vivo, 17-DMAG treatment at 25 mg/kg three times a week significantly suppresses tumor growth, and metastasis of ME180 and SiHa xenografts in mice. [4] Administration of 17-DMAG at 10 mg/kg for 16 days significantly decreases the white blood cell count and prolongs the survival in a TCL1-SCID transplant mouse model. [5]
Clinical Trials A Phase I study of 17-DMAG in treating patients with an advanced solid tumor or lymphoma has been completed. A Phase I study of the combination of intravenous 17-DMAG, Trastuzumab with or without Paclitaxel in patients with advanced solid tumor malignancies or Her2 positive metastatic breast cancer who have previously failed frastuzumab therapy has been completed.
Features 17-DMAG is a synthetic derivative of the antibiotic Geldanamycin with lower hepatotoxicity than the parent antibiotic and higher potency and availability than the similar derivative 17-AAG.
Protocol
Kinase Assay [1]
Fluorescence polarization (FP)-based competition binding assay This assay utilizes a boron difluoride dipyrromethene (BODIPY) labeled geldanamycin analogue (BODIPY-AG) as a probe and measured fluorescence polarization upon binding of the probe to a protein. Native human Hsp90 protein (α + β isoforms) is isolated from HeLa cells. BODIPY-AG solution is freshly prepared in FP assay buffer (20 mM HEPES-KOH, pH 7.3, 1.0 mM EDTA, 100 mM KCl, 5.0 mM MgCl2, 0.01% NP-40, 0.1 mg/mL fresh bovine γ-globulin (BGG), 1.0 mM fresh DTT, and protease inhibitor from stock solution in DMSO. Competition curves are obtained by mixing 10 μL each of a solution containing BODIPY-AG and Hsp90, and a serial dilution of 17-DMAG freshly prepared in FP assay buffer from stock solution in DMSO. Final concentrations are 10 nM BODIPY-AG, 40 or 60 nM Hsp90, varying concentration of 17-DMAG (0.10 nM-10 μM), and ≤0.25% DMSO in a 384-well microplate. After 3 hours incubation at 30 °C, fluorescence anisotropy (γEx = 485 nm, γEm = 535 nm) is measured on an EnVision 2100 multilabel plate reader. IC50 value of 17-DMAG is obtained from the competition curves.
Cell Assay [5]
Cell Lines Chronic lymphocytic leukemia (CLL)
Concentrations Dissolved in DMSO, final concentrations ~1 μM
Incubation Time 24, or 48 hours
Methods Cells are exposed to various concentrations of 17-DMAG for 24, or 48 hours. For the assessment of cytotoxicity, MTT reagent is then added, and plates are incubated for an additional 24 hours before spectrophotometric measurement. Apoptosis is determined by staining with annexin V-fluorescein isothiocyanate and propidium iodide (PI).
Animal Study [5]
Animal Models SCID mice engrafted with TCL1 leukemia cells
Formulation Dissolved in DMSO
Doses 10 mg/kg
Administration Intraperitoneal injection 5 times per week
References
[1] Ge J, et al. J Med Chem, 2006, 49(15), 4606-4615.
[2] Lang SA, et al. Mol Cancer Ther, 2007, 6(3), 1123-1132.
[3] Rao R, et al. Cancer Biol Ther, 2009, 8(13), 1273-1280.
[4] Schwock J, et al. Cancer Res, 2009, 69(11), 4750-4759.
[5] Hertlein E, et al. Blood, 2010, 116(1), 45-53.

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PATENTS

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