Cedazuridine
Cedazuridine Basic information
- Product Name:
- Cedazuridine
- Synonyms:
-
- (R)-1-((2R, 4R, SR)-3,3-difluoro-4-hydroxy (hydroxymethyl) tetrahydrofuran-2-yl)-4-hydroxytetrahydropyrimidin-2(1H)-one
- Cedazuridine (E7727
- E 7727)
- Uridine, 2'-deoxy-2',2'-difluoro-3,4,5,6-tetrahydro-, (4R)-
- 2’-deoxy-2’,2’-difluorotetrahydrouridine
- Clascoterone Impurity 38
- (4R)-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one
- Cedazuridine, 10 mM in DMSO
- CAS:
- 1141397-80-9
- MF:
- C9H14F2N2O5
- MW:
- 268.21
- EINECS:
- 822-329-6
- Mol File:
- 1141397-80-9.mol
Cedazuridine Chemical Properties
- Boiling point:
- 597.7±50.0 °C(Predicted)
- Density
- 1+-.0.1 g/cm3(Predicted)
- storage temp.
- 4°C, protect from light
- solubility
- DMSO : 50 mg/mL (186.42 mM; ultrasonic and warming and heat to 60°C)
- pka
- 11.72±0.70(Predicted)
- form
- Solid
- color
- White to off-white
- InChI
- InChI=1S/C9H12F2N2O5/c10-9(11)6(16)4(3-14)18-7(9)13-2-1-5(15)12-8(13)17/h4,6-7,14,16H,1-3H2,(H,12,15,17)/t4-,6-,7-/m1/s1
- InChIKey
- VQSLORATCUBFCL-QPPQHZFASA-N
- SMILES
- OC[C@H]1O[C@@H](N2CCC(=O)NC2=O)[C@](F)(F)[C@@H]1O
Cedazuridine Usage And Synthesis
Uses
Cedazuridine (E7727) (Compound 7a) is an orally active cytidine deaminase (CDA) inhibitor with an IC50 value of 0.4 μM. Cedazuridine can be used for cancer research[1].
Mechanism of action
Cedazuridine increases the half-life of decitabine by inhibiting cytosine deaminase, thereby improving the efficacy of combination therapy and having a better therapeutic effect than decitabine alone.
Synthesis
The synthesis began with the readily available protected gemcitabine precursor 244. The 6-aminopyridine was converted to the corresponding dihydrouracil 245 in 97% yield via acid-mediated transfer hydrogenation. Reduction under Luche conditions followed by treatment with methanolic ammonia reduced the amide carbonyl group and removed the two phenoxyester protecting groups to afford dihydrouracil 246 as a mixture of two diastereoisomers. Treatment of 246 with a catalytic amount of DBU in aqueous acetonitrile afforded a diastereomeric mixture in which cedaruridine and its cyclic amino alcohol 247 were present in a 9:1 ratio. Reconstitution of the undesired diastereomer 247 in a cold acetonitrile/water mixture (5:1) afforded cedaruridine in 86% yield.
in vivo
Cedazuridine (3 mg/kg; p.o.; daily for 7 days) in combination with 2.5 mg/kg AZA shows tumor regression in mice MOLM-13 CDX and PDX models[2].
| Animal Model: | Female NSGS mice, 6–8 weeks old, human cell line-derived (CDX) and primary patient-derived xenograft (PDX) models[2] |
| Dosage: | 3 mg/kg |
| Administration: | Oral administration, in combination with 2.5 mg/kg AZA, daily for 7 days |
| Result: | Led to reduction of leukemic expansion in combination with AZA in a cell line-derived xenograft transplantation, and exhibited preliminary safety and efcacy in a primary AML PDX model. |
| Animal Model: | NSGS male mice[2] |
| Dosage: | 1, 3, 10 and 30 mg/kg |
| Administration: | Oral, in combination with 2.5 mg/kg AZA (Pharmacokinetic Studies) |
| Result: | Dose-dependently increased the AUC of oral AZA and in comparison to dosing of standard i.p. AZA. |
References
[1] Ferraris D, et al. Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase. J Med Chem. 2014 Mar 27; 57(6):2582-8. DOI:10.1021/jm401856k
[2] Ramsey H E, et al. Oral azacitidine and cedazuridine approximate parenteral azacitidine efficacy in murine model. Targeted Oncology, 2020, 15(2): 231-240.
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