pentyl N-{1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl}carbamate

• ChemBase ID: 972
• Molecular Formular: C15H22FN3O6
• Molecular Mass: 359.3500832
• Monoisotopic Mass: 359.14926366
• SMILES: Fc1cn([C@@H]2O[C@@H]([C@@H](O)[C@H]2O)C)c(=O)nc1NC(=O)OCCCCC
• Canonical SMILES: CCCCCOC(=O)Nc1nc(=O)n(cc1F)[C@@H]1O[C@@H]([C@H]([C@H]1O)O)C
• InChI: InChI=1S/C15H22FN3O6/c1-3-4-5-6-24-15(23)18-12-9(16)7-19(14(22)17-12)13-11(21)10(20)8(2)25-13/h7-8,10-11,13,20-21H,3-6H2,1-2H3,(H,17,18,22,23)/t8-,10-,11-,13-/m1/s1
• InChIKey: GAGWJHPBXLXJQN-UORFTKCHSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: pentyl N-{1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl}carbamate
• IUPAC Traditional name: capecitabine; CAPE
• Brand Name: Xeloda
• Synonyms: capecitabine; R340; Capecitabine; Pentyl (1-((2R,3R,4S,5R)-3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)carbamate; Xeloda; Capecitabine(Xeloda)

Database IDs

• CAS Number: 154361-50-9
• MDL Number: MFCD00930626
• PubChem SID: 46508686; 160964435
• PubChem CID: 60953
• CHEBI ID: 31348
• ATC CODE: L01BC06
• CHEMBL: 1773
• Chemspider ID: 54916
• DrugBank ID: DB01101
• KEGG ID: D01223
• Unique Ingredient Identifier: 6804DJ8Z9U
• Wikipedia Title: Capecitabine
• Medline Plus: a699003

CALCULATED PROPERTIES

JChem

• Acid pKa: 8.226098
• H Acceptors: 6
• H Donor: 3
• LogD (pH = 5.5): 0.76731384
• LogD (pH = 7.4): 0.71495193
• Log P: 0.76803607
• Molar Refractivity: 82.746 cm^3
• Polarizability: 32.438602 Å^3
• Polar Surface Area: 120.69 Å^2
• Rotatable Bonds: 7
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 1.17
• LOG S: -3.16
• Solubility (Water): 2.48e-01 g/l

PROPERTIES

Physical Property

• Solubility: 26 mg/mL; DMSO
• Hydrophobicity(logP): 0.4

Safety Information

• Storage Condition: -20°C
• Storage Warning: IRRITANT
• TSCA Listed: false

Pharmacology Properties

• Target: Antimetabolites
• Admin Routes: Oral
• Bioavailability: Extensive
• Excretion: Renal 95.5%, faecal 2.6%
• Half Life: 38–45 minutes
• Metabolism: Hepatic, to 5'-DFCR, 5'-DFUR (inactive); neoplastic tissue, 5'-DFUR to active fluorouracil
• Protein Bound: < 60%
• Legal Status: POM (UK); Rx-only (US); S4 (Australia)
• Pregnancy Category: D (Australia); D (US)

Product Information

• Purity: 95+%
• Salt Data: Free Base

DETAILS

DrugBank - DB01101

• Drug Groups: approved; investigational
• Description: Capecitabine is an orally-administered chemotherapeutic agent used in the treatment of metastatic breast and colorectal cancers. Capecitabine is a prodrug, that is enzymatically converted to fluorouracil (antimetabolite) in the tumor, where it inhibits DNA synthesis and slows growth of tumor tissue.
• Indication: For the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen. May also be used in combination with docetaxel for the treatment of metastatic breast cancer in patients who have failed to respond to, or recurred or relasped during or following anthracycline-containing chemotherapy. Capecitabine is used alone as an adjuvant therapy following the complete resection of primary tumor in patients with stage III colon cancer when monotherapy with fluroprymidine is preferred. The use or capecitabine in combination regimens for advanced gastric cancer is currently being investigated.
• Pharmacology: Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity indicated for the treatment of metastatic breast cancer and colon cancer. It is an orally administered systemic prodrug that has little pharmacologic activity until it is converted to fluorouracil by enzymes that are expressed in higher concentrations in many tumors. Fluorouracil it then metabolized both normal and tumor cells to 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP).
• Affected Organisms: Humans and other mammals
• Biotransformation: Metabolized by thymidine phosphorylase to fluoruracil.
• Absorption: Readily absorbed through the GI tract (~70%)
• Half Life: 45-60 minutes for capecitabine and its metabolites.
• Protein Binding: < 60% (mainly albumin)
• Elimination: Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose.About 3% of the administered dose is excreted in urine as unchanged drug.
• References: Walko CM, Lindley C: Capecitabine: a review. Clin Ther. 2005 Jan;27(1):23-44. [Pubmed] ; Wagstaff AJ, Ibbotson T, Goa KL: Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer. Drugs. 2003;63(2):217-36. [Pubmed] ; Koukourakis GV, Kouloulias V, Koukourakis MJ, Zacharias GA, Zabatis H, Kouvaris J: Efficacy of the oral fluorouracil pro-drug capecitabine in cancer treatment: a review. Molecules. 2008 Aug 27;13(8):1897-922. [Pubmed] ; Twelves C: Vision of the future: capecitabine. Oncologist. 2001;6 Suppl 4:35-9. [Pubmed] ; Milano G, Ferrero JM, Francois E: Comparative pharmacology of oral fluoropyrimidines: a focus on pharmacokinetics, pharmacodynamics and pharmacomodulation. Br J Cancer. 2004 Aug 16;91(4):613-7. [Pubmed] ; de Bono JS, Twelves CJ: The oral fluorinated pyrimidines. Invest New Drugs. 2001;19(1):41-59. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1156

Research Area

• Description: Glioma,Oesophageal cancer, Colorectal cancer

Biological Activity

• Description: Capecitabine is a tumor-selective fluoropyrimidine carbamate which achieves higher intratumoral 5-FU level with lower toxicity than 5-FU.
• In Vitro: Both LS174T WT and LS174T-c2 cells show significantly greater sensitivity to Capecitabine when cultivated in the same plates as HepG2 hepatoma with IC50 values of 890 and 630 μM in LS174T WT alone and cultivated with HepG2, respectively. In addition, for the LS174T-C2 subline, the IC50 falls from 330 ± 4 down to 89 ± 6 μm when cultivated in the same plates as hepatoma cells. Furthermore, Capecitabine induces apoptosis in a Fas-dependent manner, and shows a 7-fold higher cytotoxicity and markedly stronger apoptotic potential in thymidine phosphorylase (TP)-transfected LS174T-c2 cells. ^[1]
• In Vivo: In the human cancer xenograft models studied, Capecitabine is more effective in a wider dose range and has a broader spectrum of antitumor activity than 5-FU, UFT or its intermediate metabolite 5'-DFUR, which can be correlated with tumor dThdPase levels. ^[2] Capecitabine inhibits tumor growth and metastatic recurrence after resection of human hepatocellular carcinoma (HCC) in highly metastatic nude mice model which is attributed to the high expression of platelet-derived endothelial cell growth factor in tumors. ^[3]
• Clinical Trials: Capecitabine is currently under investigation in Phase II clinical trials in patients with Breast Cancer Metastasis.
• Features: Capecitabine is a tumor-selective fluoropyrimidine carbamate.

Protocol

• Protocol: Cell Assay ^[1]
• Cell Lines: HepG2, LS174T WT and LS174T-c2 cells
• Concentrations: ~1 mM
• Incubation Time: 72 hours
• Methods: HepG2 and either LS174T WT or LS174T-c2 cells are seeded, respectively, in the top and bottom chambers of 8-well strip membranes in 96-well plates. The exponentially growing cells are exposed to increasing concentrations of capecitabine. The medium is supplemented with 750 ng/mL ZB4 MoAB or 100 ng/mL BR17 MoAB when the latter are used in the experiments. After 72 hours of continuous exposure, LS174T viability is assessed using the classic colorimetric MTT test.
• Protocol: Animal Study ^[2]
• Animal Models: BALB/c nu/nu mice are inoculated s.c. with small pieces of CXF280 xenograft tissues
• Formulation: Capecitabine is dissolved in water.
• Doses: ≤1.5 mM/kg/day
• Administration: Administered via p.o.

References

• References: [1] Ciccolini J, et al. Mol Cancer Ther. 2002, 1(11), 923-927.
• References: [2] Ishikawa T, et al. Biochem Pharmacol. 1998, 55(7), 1091-1097.
• References: [3] Zhou J, et al. Clin Cancer Res. 2003, 9(16), 6030-6037.

REFERENCES

• Walko CM, Lindley C: Capecitabine: a review. Clin Ther. 2005 Jan;27(1):23-44. Pubmed
• Wagstaff AJ, Ibbotson T, Goa KL: Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer. Drugs. 2003;63(2):217-36. Pubmed
• Koukourakis GV, Kouloulias V, Koukourakis MJ, Zacharias GA, Zabatis H, Kouvaris J: Efficacy of the oral fluorouracil pro-drug capecitabine in cancer treatment: a review. Molecules. 2008 Aug 27;13(8):1897-922. Pubmed
• Twelves C: Vision of the future: capecitabine. Oncologist. 2001;6 Suppl 4:35-9. Pubmed
• Milano G, Ferrero JM, Francois E: Comparative pharmacology of oral fluoropyrimidines: a focus on pharmacokinetics, pharmacodynamics and pharmacomodulation. Br J Cancer. 2004 Aug 16;91(4):613-7. Pubmed
• de Bono JS, Twelves CJ: The oral fluorinated pyrimidines. Invest New Drugs. 2001;19(1):41-59. Pubmed
• Ciccolini J, et al. Mol Cancer Ther. 2002, 1(11), 923-927.
• Ishikawa T, et al. Biochem Pharmacol. 1998, 55(7), 1091-1097.
• Zhou J, et al. Clin Cancer Res. 2003, 9(16), 6030-6037.