N,N'-Bis(2-bromoethyl)phosphorodiamidic acid (1-methyl-2-nitro-1H-imidazol-5-yl)methyl ester
N,N'-Bis(2-bromoethyl)phosphorodiamidic acid (1-methyl-2-nitro-1H-imidazol-5-yl)methyl ester Basic information
- Product Name:
- N,N'-Bis(2-bromoethyl)phosphorodiamidic acid (1-methyl-2-nitro-1H-imidazol-5-yl)methyl ester
- Synonyms:
-
- N,N'-Bis(2-bromoethyl)phosphorodiamidic acid (1-methyl-2-nitro-1H-imidazol-5-yl)methyl ester
- TH 302
- EvofosfaMide
- TH-302, >=98%
- TH-302 (Evofosfamide)
- (1-methyl-2-nitro-1H-imidazol-5-yl)methylN,N'-bis(2-bromoethyl)diamidophosphate
- EOS-61724
- Evofosfamide(TH 302)
- CAS:
- 918633-87-1
- MF:
- C9H16Br2N5O4P
- MW:
- 449.04
- Product Categories:
-
- TH-302
- APIs
- API
- Mol File:
- 918633-87-1.mol
N,N'-Bis(2-bromoethyl)phosphorodiamidic acid (1-methyl-2-nitro-1H-imidazol-5-yl)methyl ester Chemical Properties
- Melting point:
- 97-98°C
- Boiling point:
- 565.4±60.0 °C(Predicted)
- Density
- 1.97
- storage temp.
- Hygroscopic, -20°C Freezer, Under inert atmosphere
- solubility
- DMSO (Slightly), Methanol (Slightly)
- pka
- 0.34±0.70(Predicted)
- form
- Solid
- color
- Off-White to Pale Yellow
- InChI
- InChI=1S/C9H16Br2N5O4P/c1-15-8(6-12-9(15)16(17)18)7-20-21(19,13-4-2-10)14-5-3-11/h6H,2-5,7H2,1H3,(H2,13,14,19)
- InChIKey
- UGJWRPJDTDGERK-UHFFFAOYSA-N
- SMILES
- P(NCCBr)(NCCBr)(OCC1N(C)C([N+]([O-])=O)=NC=1)=O
N,N'-Bis(2-bromoethyl)phosphorodiamidic acid (1-methyl-2-nitro-1H-imidazol-5-yl)methyl ester Usage And Synthesis
Description
TH-302 is a hypoxia-activated prodrug and DNA alkylating agent with anticancer activity. It is selectively cytotoxic to H460 human non-small cell lung cancer (NSCLC) cells grown under hypoxic over normoxic conditions (IC50s = 0.019 and 5.1 μM, respectively). Under hypoxic conditions, TH-302 undergoes a one-electron reduction to form an active radical intermediate that is then further reduced to form a DNA-intercalating hydroxylamine. Under normoxic conditions, the radical intermediate is quenched and induces reformation of the inactive nitroazole prodrug. TH-302 reduces survival of H460 and HT-29 cells in a clonogenic assay (IC50s = 0.2 and 0.2 μM, respectively). In vivo, TH-302 (33 mg/kg per day) inhibits primary tumor growth by 41% in an MIA PaCa-2-RFP mouse orthotopic xenograft model. It inhibits tumor growth by greater than 40% in Calu-6 NSCLC, H82 small cell lung, A375 melanoma, PC-3 prostate, and BxPC-3 pancreatic cancer mouse xenograft models when administered at 50 mg/kg.
Uses
TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP) of bromo-isophosphoramide mustard. Studies have shown that TH-302 treatment exhibited hypoxia-selective cytotoxicity and DNA damage in human cancer cell
in vivo
Evofosfamide (TH-302) is a hypoxia-activated prodrug known to activate selectively under the hypoxic conditions commonly found in solid tumors. The mean values of normalized Ktrans decrease 69.2% for Evofosfamide (TH-302)-treated mice in Hs766t tumors, decrease 46.1% for Mia PaCa-2 tumors and increase 4.9% in SU.86.86 tumors. Both changes for Hs766t and Mia PaCa-2 treatment groups are statistically significant (P<0.01) when compare to their own control group[2]. A significant reduction in the hypoxic fraction (HF) to 2.1%±4.7% is seen after 95% oxygen breathing (P<0.001), whereas 7% oxygen breathing significantly increase the HF to 29.5%±14.7% (P=0.029). Exposing rhabdomyosarcoma-bearing rats to increasing oxygen conditions abolish the effect of TH-302 and reduce the T4×SV from 20.4±3.5 to 15.3±2.5 days (P=0.007), whereas control animals have an increased T4×SV. Upon combination with radiotherapy, the T4×SV of TH-302-treated tumors decrease from 30.8±5.9 (Evofosfamide (TH-302)+radiotherapy) to 25.7±2.9 days (Evofosfamide (TH-302)+radiotherapy+95% O2)[3].
storage
Store at -20°C
References
[1] JIAN-XIN DUAN*. Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs[J]. Journal of Medicinal Chemistry, 2008, 51 8: 2412-2420. DOI: 10.1021/jm701028q
[2] JESSICA D SUN. Selective tumor hypoxia targeting by hypoxia-activated prodrug TH-302 inhibits tumor growth in preclinical models of cancer.[J]. Clinical Cancer Research, 2012, 18 3: 758-770. DOI: 10.1158/1078-0432.ccr-11-1980
N,N'-Bis(2-bromoethyl)phosphorodiamidic acid (1-methyl-2-nitro-1H-imidazol-5-yl)methyl esterSupplier
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