4-amino-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one hydrochloride

• ChemBase ID: 72545
• Molecular Formular: C9H12ClF2N3O4
• Molecular Mass: 299.6590864
• Monoisotopic Mass: 299.04844
• SMILES: c1(=O)nc(ccn1[C@@H]1O[C@@H]([C@H](C1(F)F)O)CO)N.Cl
• Canonical SMILES: OC[C@H]1O[C@H](C([C@@H]1O)(F)F)n1ccc(nc1=O)N.Cl
• InChI: InChI=1S/C9H11F2N3O4.ClH/c10-9(11)6(16)4(3-15)18-7(9)14-2-1-5(12)13-8(14)17;/h1-2,4,6-7,15-16H,3H2,(H2,12,13,17);1H/t4-,6-,7-;/m1./s1
• InChIKey: OKKDEIYWILRZIA-OSZBKLCCSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 4-amino-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one hydrochloride
• IUPAC Traditional name: gemcitabine hydrochloride
• Synonyms: Gemzar; Gemcitabine Hydrochloride; Gemzar (Lilly); LY-188011; dFdC; dFdCyd; Gemcitabine hydrochloride; 2′-Deoxy-2′,2′-difluorocytidine; dFdC

Database IDs

• CAS Number: 122111-03-9
• MDL Number: MFCD01735988
• PubChem SID: 162037470
• PubChem CID: 60749

CALCULATED PROPERTIES

• Acid pKa: 11.51707
• H Acceptors: 6
• H Donor: 3
• LogD (pH = 5.5): -1.4665402
• LogD (pH = 7.4): -1.4665728
• Log P: -1.4665396
• Molar Refractivity: 53.2503 cm^3
• Polarizability: 20.563793 Å^3
• Polar Surface Area: 108.38 Å^2
• Rotatable Bonds: 2
• Lipinski's Rule of Five: true

PROPERTIES

Physical Property

• Solubility: DMSO; H2O: ≥10 mg/mL
• Apperance: powder

Safety Information

• Storage Condition: -20°C; desiccated; protect from light
• European Hazard Symbols: Harmful (Xn)
• German water hazard class: 3
• Risk Statements: 63-62
• Safety Statements: 53-36/37
• GHS Pictograms: GHS08
• GHS Signal Word: Danger
• GHS Hazard statements: H360
• GHS Precautionary statements: P201-P308 + P313
• Storage Temperature: room temp

Pharmacology Properties

• Target: Antimetabolites

Product Information

• Purity: ≥98% (HPLC); 95+%
• Salt Data: Hydrochloride
• Empirical Formula (Hill Notation): C9H11F2N3O4 · HCl

DETAILS

Selleck Chemicals - S1149

Research Area

• Description: Cancer

Biological Activity

• Description: Gemcitabine Hydrochloride (Gemzar) is a DNA synthesis inhibitor with IC50 of 50 nM, 40 nM, 18 nM and 12 nM in PANC1, MIAPaCa2, BxPC3 and Capan2 cell lines, respectively.
• Targets: PANC1; MIAPaCa2; BxPC3; Capan2 cell lines
• IC50: 50 nM; 40 nM; 18 nM; 12 nM ^[1]
• In Vitro: Gemcitabine induced NF-κB activity in BxPC-3, PANC-1, and MIA PaCa-2 cells and decreased the level of the NF-κB inhibitor IκBα in BxPC-3 and PANC-1 cells. Treatment of BxPC-3 cells with low dose Gemcitabine for 48 hours results in a dose-dependent increase in NF-κB binding. In contrast, NF-κB DNA binding is decreased in BxPC-3 cells treated with the higher Gemcitabine doses for 48 h; however, 24-h treatment with these higher doses increases NF-κB binding in BxPC-3 cells ^[2]
• In Vivo: Intratumoral NF-κB activity is significantly elevated (1.3- to 1.8-fold) in the Gemcitabine-treated mice compared to the PBS-treated mice, suggesting that Gemcitabine also induces NF-κB activation. ^[2]
• Clinical Trials: Gemcitabine plus PEGPH20 has entered in a phase II clinical trial in the treatmentof the stage IV pancreatic cancer.
• Features: Gemcitabine has been used for pancreatic cancer as the most effective anticancer drug.

Combination Therapy

• Description: The combination of P276 (a CDK inhibitor) and Gemcitabine results in a dose- and time-dependent inhibition of proliferation and colony formation of pancreatic cancer cells but not with normal pancreatic ductal cells. This combination also induces apoptosis and increases Bax/Bcl2 ratio. ^[3]Combined therapy of Gemcitabine with IFN-γ in Gemcitabine-resistant pancreatic cancer-bearing nude mice shows synergistic therapeutic effects on Gemcitabine-resistant pancreatic cancer bearers. ^[4] The addition of Triciribine can sensitize Gemcitabine treatment, especially in shFKBP5 pancreatic cancer xenograft mice. Combination treatment with Gemcitabine and Triciribine has a better effect on tumor inhibition than either drug alone and that the inhibition effect is more significant in shFKBP5 xenograft mice than wt mice. ^[5] Combination of Guggulsterone (a plant steroid) to Gemcitabine enhances antitumor efficacy. ^[6] Gemcitabine with adjuvant chemotherapy is currently being investigated in a Phase III clinical trial for the treatment of resected pancreatic adenocarcinoma.

Protocol

• Protocol: Cell Assay ^[2]
• Cell Lines: BxPC-3, MIA PaCa-2, and PANC-1 cells
• Concentrations: 0.2 μM
• Incubation Time: 24 hours or 48 hours
• Methods: BxPC-3, MIA PaCa-2, and PANC-1 cells are seeded in a 96-well plate. After 24 hours, cells are treated with vehicle, DMAPT and/or Gemcitabine for an additional 24 hours or 48 hours. Apoptosis is quantified using the Cell Death Detection ELISA to detect the amount of cytoplasmic histone-associated DNA fragments and expressed relative to vehicle-treated cells.
• Protocol: Animal Study ^[2]
• Animal Models: Athymic nude mice with MIA PaCa-2 cells
• Formulation: Phosphate-buffered saline
• Doses: 50 mg/kg or 100 mg/kg
• Administration: Administered via i.p.

References

• References: [1] Shi X, et al. Oncology. 2002, 62(4), 354-362.
• References: [2] Holcomb BK, et al. J Gastrointest Surg. 2012.
• References: [3] Subramaniam D, et al. Mol Cancer Ther. 2012.
• References: [4] Kuramitsu Y, et al. Anticancer Res. 2012, 32(6), 2295-2299.
• References: [5] Hou J, et al. PLoS One. 2012, 7(5), e36252.
• References: [6] Ahn DW, et al. Pancreas. 2012.

Sigma Aldrich - G6423

Biochem/physiol Actions
Gemcitabine is a widely used antitumor agents in both clinics and research labs. It is an antineoplastic agent and antimetabolite.

REFERENCES

• Kuramitsu Y, et al. Anticancer Res. 2012, 32(6), 2295-2299.
• Shi X, et al. Oncology. 2002, 62(4), 354-362.
• Holcomb BK, et al. J Gastrointest Surg. 2012.
• Subramaniam D, et al. Mol Cancer Ther. 2012.
• Hou J, et al. PLoS One. 2012, 7(5), e36252.
• Ahn DW, et al. Pancreas. 2012.