6,8-dioxa-7-platinaspiro[3.5]nonane-5,9-dione diamine

• ChemBase ID: 834
• Molecular Formular: C6H12N2O4Pt
• Molecular Mass: 371.24848
• Monoisotopic Mass: 371.04449787
• SMILES: C1CCC21C(=O)O[Pt]OC2=O.N.N
• Canonical SMILES: O=C1O[Pt]OC(=O)C21CCC2.N.N
• InChI: InChI=1S/C6H8O4.2H3N.Pt/c7-4(8)6(5(9)10)2-1-3-6;;;/h1-3H2,(H,7,8)(H,9,10);2*1H3;/q;;;+2/p-2
• InChIKey: OLESAACUTLOWQZ-UHFFFAOYSA-L

NAMES AND DATABASE IDS

Names

• IUPAC name: 6,8-dioxa-7-platinaspiro[3.5]nonane-5,9-dione diamine
• IUPAC Traditional name: 6,8-dioxa-7-platinaspiro[3.5]nonane-5,9-dione diamine
• Brand Name: Paraplatin; Paraplatin-AQ
• Synonyms: cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II); CBDCA; Carboplatin; Paraplatin; cis-Diammine(1,1-cyclobutanedicarboxylato) platinum; Carboplatin

Database IDs

• CAS Number: 41575-94-4
• EC Number: 255-446-0
• MDL Number: MFCD00070464
• PubChem SID: 160964297; 46507170; 24278303
• PubChem CID: 38904; 498142
• CHEBI ID: 31355
• ATC CODE: L01XA02
• CHEMBL: 288376
• Chemspider ID: 8514637
• DrugBank ID: DB00958
• KEGG ID: D01363
• Unique Ingredient Identifier: BG3F62OND5
• Wikipedia Title: Carboplatin
• Medline Plus: a695017

CALCULATED PROPERTIES

• H Acceptors: 2
• H Donor: 0
• LogD (pH = 5.5): 1.0637
• LogD (pH = 7.4): 1.0637
• Log P: 1.0637
• Molar Refractivity: 29.0069 cm^3
• Polarizability: 19.593359 Å^3
• Polar Surface Area: 52.6 Å^2
• Rotatable Bonds: 0
• Lipinski's Rule of Five: true

PROPERTIES

Physical Property

• Solubility: DMSO

Safety Information

• Storage Condition: -20°C
• RTECS: TP2300000
• European Hazard Symbols: Toxic (T)
• German water hazard class: 3
• Risk Statements: 46-61-20/21/22-42/43
• Safety Statements: 53-22-26-36/37/39-45
• GHS Pictograms: GHS07; GHS08
• GHS Signal Word: Danger
• GHS Hazard statements: H302 + H312 + H332-H317-H334-H360
• GHS Precautionary statements: P201-P261-P280-P308 + P313
• Personal Protective Equipment: Eyeshields, Faceshields, full-face particle respirator type N100 (US), Gloves, respirator cartridge type N100 (US), type P1 (EN143) respirator filter, type P3 (EN 143) respirator cartridges

Pharmacology Properties

• Target: DNA/RNA synthesis
• Admin Routes: Intravenous
• Bioavailability: complete
• Excretion: renal
• Half Life: 1.1-2 hours
• Protein Bound: Very low
• Legal Status: Rx Only
• Pregnancy Category: D (US)

Product Information

• Salt Data: Free Base

DETAILS

DrugBank - DB00958

• Drug Groups: approved
• Description: An organoplatinum compound that possesses antineoplastic activity. [PubChem]
• Indication: For the initial treatment of advanced ovarian carcinoma in established combination with other approved chemotherapeutic agents. One established combination regimen consists of PARAPLATIN and cyclophosphamide.
• Pharmacology: Carboplatin is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.
• Toxicity: Toxic by ingestion. May be create toxic effect through inhalation or skin contact. May cause reproductive defects. May act as a sensitizer.; ORL-RAT LD₅₀ 343 mg kg-1; SCN-RAT LD₅₀ 72 mg kg-1; IPN-MUS LD₅₀ 118 mg kg-1
• Affected Organisms: Humans and other mammals
• Half Life: 1.1-2 hours
• Protein Binding: Very low
• Elimination: The major route of elimination of carboplatin is renal excretion.
• Distribution: * 16 L
• Clearance: * 4.4 L/h [Patients with Clcr >= 60 mL/min receiving IV infusion of 300 to 500 mg/m2]
• References: Natarajan G, Malathi R, Holler E: Increased DNA-binding activity of cis-1,1-cyclobutanedicarboxylatodiammineplatinum(II) (carboplatin) in the presence of nucleophiles and human breast cancer MCF-7 cell cytoplasmic extracts: activation theory revisited. Biochem Pharmacol. 1999 Nov 15;58(10):1625-9. [Pubmed] ; Knox RJ, Friedlos F, Lydall DA, Roberts JJ: Mechanism of cytotoxicity of anticancer platinum drugs: evidence that cis-diamminedichloroplatinum(II) and cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II) differ only in the kinetics of their interaction with DNA. Cancer Res. 1986 Apr;46(4 Pt 2):1972-9. [Pubmed] ; Canetta R, Rozencweig M, Carter SK: Carboplatin: the clinical spectrum to date. Cancer Treat Rev. 1985 Sep;12 Suppl A:125-36. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1215

Research Area

• Description: Cancer

Biological Activity

• Description: Carboplatin is a DNA synthesis inhibitor by binding to DNA and interfering with the cell's repair mechanism.
• In Vitro: Carboplatin exhibits an inhibitory effect on cell proliferation in a human ovarian cancer cell line panel, including A2780, SKOV3, and IGROV-1 cells with IC50 of 6.1 μM, 12.4 μM and 2.2 μM, respectively. ^[2] Carboplatin also show the anti-proliferative activities in lung carcinoid cell line, such as UMC-11, H727, and H835 cells with IC50 of 36.4 μM, 3.4 μM and 35.8 μM, respectively. ^[4]
• In Vivo: In A2780 tumor xenografts, Carboplatin (60 mg/kg via i.p.) given as single agents shows a modest antitumor effect with the relative tumor volumes on day 6 of 8.4 compared to the control of 11.9, and the day 6 tumor weights relative to control (T/C) of 67%. ^[2] For the VC8 (Brca2-deficient) xenografts, Carboplatin treatment delays tumor growth and reduces tumor mass by 42% compared to the vehicle group. ^[5]
• Clinical Trials: Carboplatin is currently in Phase II clinical trials in patients with Recurrent, Ovary, Fallopian Tube, and Primary Peritoneal Cancer.
• Features: Carboplatin is a DNA synthesis inhibitor.

Combination Therapy

• Description: Combination of Dexamethasone and Carboplatin shows a more markedly antitumor effects by 2–4-fold than either drug alone in LS174T (colon), MCF-7 and MDA-MB-468 (breast), A549 (lung) and glioma (U87-MG) xenograft models. ^[1] For A2780 cells, the concomitant treatment of hsp90 inhibitor 17-AAG and Carboplatin shows an antagonistic activity against cell proliferation with CI of 2.8. While combination treatment of 17-AAG and Carboplatin in different sequences leads to an additive inhibitory effect on cell proliferation with CI of 0.96 and 0.97 for the sequence 17-AAG followed by Carboplatin and Carboplatin followed by 17-AAG, respectively. ^[2] A recent study shows that mTOR inhibitor RAD001 in combination with Carboplatin results in synergistic inhibition of cell proliferation and caspase-independent apoptosis in breast cancer cell lines including MCF-7, tamoxifen-resistant MCF-7, and ZR-75 (all wild-type p53), SKBR-3 and BT-474 cell lines (all p53-mutated) with CI at EC50 of 0.228, 0.611, 0.599, 0.623 and 0.423, respectively. ^[3]Everolimus in combination with Paclitaxel and Carboplatin is currently in Phase II clinical trials in patients with Metastatic Melanoma.

Protocol

• Protocol: Cell Assay ^[2]
• Cell Lines: A2780, SKOV3, IGROV-1 and HX62
• Concentrations: 0-200 μM
• Incubation Time: 72 hours
• Methods: 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assays: Exponentially growing A2780, SKOV3, IGROV-1 and HX62 ovarian cancer cells are plated in 96 well plates. A range of drug concentrations are added and the plates are incubated for 72 hours to allow for 3–4 doubling times. Each experiment is carried out in triplicate. Sulforhodamine B (SRB) assays: Exponentially growing A2780 cells are plated in 96 well microtitre plates. For experiments studying concomitant exposure, cells are exposed to increasing concentrations of both drugs for 96 hours. For experiments studying the effect of sequence of exposure to 17-AAG or carboplatin cells are exposed to increasing concentrations of 17-AAG or carboplatin for 24 hours. A period of 24-hour exposure to the first agent is chosen so that the A2780 cells would be exposed to the first drug for at least one doubling time (18-24 hours). The cells are then washed with sterile phosphate buffered saline and the medium is replenished. Following this, the second drug (to which the cells are not exposed to in the first 24 hours) or medium is added for 96 hours. All experiments are carried out in triplicate. The results of combination studies are analyzed using the well-established principles of median effect analysis method. The effects of the combination are calculated using an in-house spreadsheet.
• Protocol: Animal Study ^[2]
• Animal Models: The A2780 human ovarian cancer cell line is grown as a subcutaneous xenograft in female athymic NCr nude mice (nu/nu) in each flank.
• Formulation: Carboplatin is dissolved in 43% ethanol, 33% polypropylene glycol and 24% cremaphor diluted 1:7 with sterile water.
• Doses: ≤60 mg/kg
• Administration: Administered via i.p.

References

• References: [1] Wang H, et al. Clin Cancer Res. 2004, 10(5), 1633-1644.
• References: [2] Banerji U, et al. Cancer Chemother Pharmacol. 2008, 62(5), 769-778.
• References: [3] Liu H, et al. Anticancer Res. 2011, 31(9), 2713-2722.
• References: [4] Fiebiger W, et al. Clin Transl Oncol. 2011, 13(1), 43-49.
• References: [5] Clark CC, et al. Mol Cancer Ther, 2012, doi: 10.1158/1535-7163.MCT-11-0597.

Sigma Aldrich - C2538

Biochem/physiol Actions
Carboplatin is a platinum-based antineoplastic drug that damages DNA by forming intrastrand cross-links with neighboring guanine residues. Tumors acquire resistance to these drugs through the loss of DNA-mismatch repair (MMR) activity and the resultant decrease in the induction of programmed cell death.

REFERENCES

• Knox RJ, Friedlos F, Lydall DA, Roberts JJ: Mechanism of cytotoxicity of anticancer platinum drugs: evidence that cis-diamminedichloroplatinum(II) and cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II) differ only in the kinetics of their interaction with DNA. Cancer Res. 1986 Apr;46(4 Pt 2):1972-9. Pubmed
• Canetta R, Rozencweig M, Carter SK: Carboplatin: the clinical spectrum to date. Cancer Treat Rev. 1985 Sep;12 Suppl A:125-36. Pubmed
• Natarajan G, Malathi R, Holler E: Increased DNA-binding activity of cis-1,1-cyclobutanedicarboxylatodiammineplatinum(II) (carboplatin) in the presence of nucleophiles and human breast cancer MCF-7 cell cytoplasmic extracts: activation theory revisited. Biochem Pharmacol. 1999 Nov 15;58(10):1625-9. Pubmed
• Fiebiger W, et al. Clin Transl Oncol. 2011, 13(1), 43-49.
• Clark CC, et al. Mol Cancer Ther, 2012, doi: 10.1158/1535-7163.MCT-11-0597.
• Wang H, et al. Clin Cancer Res. 2004, 10(5), 1633-1644.
• Banerji U, et al. Cancer Chemother Pharmacol. 2008, 62(5), 769-778.
• Liu H, et al. Anticancer Res. 2011, 31(9), 2713-2722.