4-[(2S)-1-(3,5-dioxopiperazin-1-yl)propan-2-yl]piperazine-2,6-dione

• ChemBase ID: 264
• Molecular Formular: C11H16N4O4
• Molecular Mass: 268.26914
• Monoisotopic Mass: 268.11715501
• SMILES: O=C1NC(=O)CN([C@H](CN2CC(=O)NC(=O)C2)C)C1
• Canonical SMILES: O=C1NC(=O)CN(C1)C[C@@H](N1CC(=O)NC(=O)C1)C
• InChI: InChI=1S/C11H16N4O4/c1-7(15-5-10(18)13-11(19)6-15)2-14-3-8(16)12-9(17)4-14/h7H,2-6H2,1H3,(H,12,16,17)(H,13,18,19)/t7-/m0/s1
• InChIKey: BMKDZUISNHGIBY-ZETCQYMHSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 4-[(2S)-1-(3,5-dioxopiperazin-1-yl)propan-2-yl]piperazine-2,6-dione; 4-[(2S)-2-(3,5-dioxopiperazin-1-yl)propyl]piperazine-2,6-dione
• IUPAC Traditional name: 4-[(2S)-1-(3,5-dioxopiperazin-1-yl)propan-2-yl]piperazine-2,6-dione; dexrazoxane
• Brand Name: Cardioxane; Dyzoxane; Eucardion; Razoxane; Razoxin; Tepirone; Troxozone; Zinecard
• Synonyms: Dexrazoxano [INN-Spanish]; Dexrazoxanum [INN-Latin]; Dextrorazoxane; Desrazoxane; Razoxana [INN-Spanish]; Razoxanum [INN-Latin]; Icrf-187; Dexrazoxane; (+)-(S)-4,4′-Propylenedi-2,6-piperazinedione; (S)-(+)-1,2-Bis(3,5-dioxopiperazin-1-yl)propane; Cardioxane; NSC169780; Zinecard; Dexrazoxane; (S)-4,4'-(Propane-1,2-diyl)bis(piperazine-2,6-dione)

Database IDs

• CAS Number: 24584-09-6
• MDL Number: MFCD00866449
• PubChem SID: 160963727; 46505982
• PubChem CID: 71384

CALCULATED PROPERTIES

JChem

• Acid pKa: 11.198792
• H Acceptors: 6
• H Donor: 2
• LogD (pH = 5.5): -2.6580358
• LogD (pH = 7.4): -2.6527913
• Log P: -2.652655
• Molar Refractivity: 64.2532 cm^3
• Polarizability: 25.298058 Å^3
• Polar Surface Area: 98.82 Å^2
• Rotatable Bonds: 3
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: -1.05
• LOG S: -1.41
• Solubility (Water): 1.04e+01 g/l

PROPERTIES

Physical Property

• Solubility: DMSO: >20 mg/mL; Sparingly soluble
• Apperance: white to off-white powder
• Hydrophobicity(logP): -2.6

Safety Information

• European Hazard Symbols: Irritant (Xi)
• UN Number: 2811
• German water hazard class: 3
• Hazard Class: 6.1
• Packing Group: 3
• Risk Statements: 36/37/38
• Safety Statements: 26-36
• GHS Pictograms: GHS07
• GHS Signal Word: Warning
• GHS Hazard statements: H315-H319-H335
• GHS Precautionary statements: P261-P305 + P351 + P338
• RID/ADR: UN 2811 6.1/PG 3
• Storage Temperature: room temp

Product Information

• Purity: ≥95% (HPLC); 95+%; 97%
• Empirical Formula (Hill Notation): C11H16N4O4

DETAILS

DrugBank - DB00380

• Drug Groups: approved
• Description: An antimitotic agent with immunosuppressive properties. Dexrazoxane, the (+)-enantiomorph of razoxane, provides cardioprotection against anthracycline toxicity. It appears to inhibit formation of a toxic iron-anthracycline complex. [PubChem]; The Food and Drug Administration has designated dexrazoxane as an orphan drug for use in the prevention or reduction in the incidence and severity of anthracycline-induced cardiomyopathy.
• Indication: For reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin hydrochloride dose of 300 mg/m^2 and would benefit from continued doxorubicin therapy. Also approved for the treatment of extravasation from intravenous anthracyclines.
• Pharmacology: Dexrazoxane is a cardioprotective agent for use in conjunction with doxorubicin indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose. Patients receiving anthracycline-derivative antineoplastic agents may experience three types of cardiotoxicity: acute transient type; chronic, subacute type (related to cumulative dose and has a more indolent onset later on); and a late-onset type that manifests years after therapy, mainly in patients that have been exposed to the drug as a child. Although the exact mechanism of anthracycline-induced cardiotoxicity is not known, it has shown to exert a variety of actions that may result in the development of cardiotoxicity. In animals, anthracyclines cause a selective inhibition of cardiac muscle gene expression for α-actin, troponin, myosin light-chain 2, and the M isoform of creatine kinase. This may lead to myofibrillar loss associated with anthracycline-induced cardiotoxicity. Anthracyclines may also cause myocyte damage via calcium overload, altered myocardial adrenergic function, release of vasoactive amines, and proinflammatory cytokines. Furthermore, it has been suggested that the main cause of anthracycline-induced cardiotoxicity is associated with free-radical damage to DNA. The drugs intercalate DNA, chelate metal ions to produce drug-metal complexes, and generate superoxide radicals via oxidation-reduction reactions. Anthracyclines also contain a quinone structure that can undergo reduction via NADPH-dependent reactions to produce a semiquinone free radical that initiates a cascade of superoxide and hydroxide radical generation. Chelation of metal ions, particularly iron, by anthracyclines results in an anthracycline-metal complex that catalyzes the generation of reactive oxygen free radicals. This complex is a powerful oxidant that can initiate lipid peroxidation in the absence of oxygen free radicals. The toxicity induced by antrhacyclines may be exacerbated in cardiac cells, as these cells do not possess sufficient amounts of certain enzymes (e.g., superoxide dismutase, catalase, glutathione peroxidase) involved in detoxifying free radicals and protecting the cells from subsequent damage.
• Toxicity: Intraperitoneal, mouse LD₁₀ = 500 mg/kg. Intravenous, dog LD₁₀ = 2 gm/kg.
• Affected Organisms: Humans and other mammals
• Biotransformation: Dexrazoxane is hydrolysed by the enzyme dihydropyrimidine amidohydrolase in the liver and kidney to active metabolites that are capable of binding to metal ions.
• Absorption: IV administration results in complete bioavailability.
• Half Life: 2.5 hours
• Protein Binding: Very low (< 2%)
• Elimination: Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent of the 500 mg/m2 dose of dexrazoxane was excreted in the urine.
• Distribution: * 9 to 22.6 L/m^2
• Clearance: * 7.88 L/h/m2 [dose of 50 mg/m2 Doxorubicin and 500 mg/m2 Dexrazoxane]; * 6.25 L/h/m2 [dose of 60 mg/m2 Doxorubicin and 600 mg/m2 Dexrazoxane]
• References: Hasinoff BB, Herman EH: Dexrazoxane: how it works in cardiac and tumor cells. Is it a prodrug or is it a drug? Cardiovasc Toxicol. 2007;7(2):140-4. [Pubmed] ; Hasinoff BB: The use of dexrazoxane for the prevention of anthracycline extravasation injury. Expert Opin Investig Drugs. 2008 Feb;17(2):217-23. [Pubmed] ; Kik K, Szmigiero L: [Dexrazoxane (ICRF-187)--a cardioprotectant and modulator of action of some anticancer drugs] Postepy Hig Med Dosw (Online). 2006;60:584-90. [Pubmed] ; Weiss G, Loyevsky M, Gordeuk VR: Dexrazoxane (ICRF-187). Gen Pharmacol. 1999 Jan;32(1):155-8. [Pubmed] ; Langer SW: Dexrazoxane for anthracycline extravasation. Expert Rev Anticancer Ther. 2007 Aug;7(8):1081-8. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Sigma Aldrich - D1446

Biochem/physiol Actions
Dexrazoxane is a cardioprotective compound against anthracyclines. It functions by inhibiting topoisomerase II without inducing DNA strand breaks. Dexrazoxane is a + enantiomer of razoxane.

REFERENCES

• Hasinoff BB, Herman EH: Dexrazoxane: how it works in cardiac and tumor cells. Is it a prodrug or is it a drug? Cardiovasc Toxicol. 2007;7(2):140-4. Pubmed
• Hasinoff BB: The use of dexrazoxane for the prevention of anthracycline extravasation injury. Expert Opin Investig Drugs. 2008 Feb;17(2):217-23. Pubmed
• Kik K, Szmigiero L: [Dexrazoxane (ICRF-187)--a cardioprotectant and modulator of action of some anticancer drugs] Postepy Hig Med Dosw (Online). 2006;60:584-90. Pubmed
• Langer SW: Dexrazoxane for anthracycline extravasation. Expert Rev Anticancer Ther. 2007 Aug;7(8):1081-8. Pubmed
• Weiss G, Loyevsky M, Gordeuk VR: Dexrazoxane (ICRF-187). Gen Pharmacol. 1999 Jan;32(1):155-8. Pubmed