(8S,10S)-10-{[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy}-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-5,7,8,9,10,12-hexahydrotetracene-5,12-dione hydrochloride

• ChemBase ID: 72574
• Molecular Formular: C27H30ClNO11
• Molecular Mass: 579.9802
• Monoisotopic Mass: 579.15073847
• SMILES: c1ccc2c(c1OC)C(=O)c1c(C2=O)c(c2c(c1O)[C@H](C[C@@](C2)(C(=O)CO)O)O[C@H]1C[C@@H]([C@@H]([C@@H](O1)C)O)N)O.Cl
• Canonical SMILES: OCC(=O)[C@@]1(O)C[C@H](O[C@H]2C[C@H](N)[C@@H]([C@@H](O2)C)O)c2c(C1)c(O)c1c(c2O)C(=O)c2c(C1=O)cccc2OC.Cl
• InChI: InChI=1S/C27H29NO11.ClH/c1-10-22(31)13(28)6-17(38-10)39-15-8-27(36,16(30)9-29)7-12-19(15)26(35)21-20(24(12)33)23(32)11-4-3-5-14(37-2)18(11)25(21)34;/h3-5,10,13,15,17,22,29,31,33,35-36H,6-9,28H2,1-2H3;1H/t10-,13-,15-,17-,22+,27-;/m0./s1
• InChIKey: MWWSFMDVAYGXBV-RUELKSSGSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (8S,10S)-10-{[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy}-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-5,7,8,9,10,12-hexahydrotetracene-5,12-dione hydrochloride
• IUPAC Traditional name: doxorubicin hydrochloride; (8S,10S)-10-{[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy}-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-5,7,8,9,10,12-hexahydrotetracene-5,12-dione hydrochloride
• Synonyms: DOX; Hydroxydaunorubicin hydrochloride; Doxorubicin hydrochloride; Doxorubicin Hydrochloride; Rubex; Adriamycin; Adriamycin; 多柔比星® 盐酸盐; 羟基柔红霉素 盐酸盐; 阿霉素 盐酸盐

Database IDs

• CAS Number: 25316-40-9
• EC Number: 246-818-3
• MDL Number: MFCD00077757
• Beilstein Number: 4229251
• PubChem SID: 162037499; 24868204
• PubChem CID: 443939

CALCULATED PROPERTIES

• Acid pKa: 9.53088
• H Acceptors: 12
• H Donor: 6
• LogD (pH = 5.5): -1.4428744
• LogD (pH = 7.4): -0.27556196
• Log P: 0.91642165
• Molar Refractivity: 134.5937 cm^3
• Polarizability: 52.692078 Å^3
• Polar Surface Area: 206.07 Å^2
• Rotatable Bonds: 5
• Lipinski's Rule of Five: false

PROPERTIES

Physical Property

• Solubility: DMSO; DMSO: soluble; ethanol: soluble; H2O: soluble50 mg/mL, clear, orange to red; methanol: soluble; THF: soluble
• Melting Point: 216 °C (dec.)(lit.)
• Fluorescence: λex 470 nm; λem 585 nm in ethanol

Safety Information

• Storage Condition: -20°C
• RTECS: QI9295900
• European Hazard Symbols: Toxic (T); Irritant (Xi)
• German water hazard class: 3
• Risk Statements: 45-22-36/38
• Safety Statements: 53-45
• GHS Pictograms: GHS07; GHS08
• GHS Signal Word: Danger
• GHS Hazard statements: H302-H315-H319-H350
• GHS Precautionary statements: P201-P305 + P351 + P338-P308 + P313
• Personal Protective Equipment: Eyeshields, full-face particle respirator type N100 (US), Gloves, respirator cartridge type N100 (US), type P1 (EN143) respirator filter, type P3 (EN 143) respirator cartridges
• Storage Temperature: 2-8°C

Pharmacology Properties

• Target: Topoisomerase
• Mechanism of Action: Forms complexes with DNA by intercalation between base pairs; Inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes; May also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA

Product Information

• Purity: 98.0-102.0% (HPLC)
• Salt Data: HCL; HCl
• Suitability: suitable for fluorescence
• Biological Source: Metab. of Streptomyces peucetius
• Application(s): Antineoplastic antibiotic; Possesses an antitumor effect against a wide spectrum of tumors; Shows anti-HIV activity; Used in the treatment of ovarian cancer and AIDS related Kaposi sarcoma
• Empirical Formula (Hill Notation): C27H29NO11 · HCl

DETAILS

Selleck Chemicals - S1208

Research Area

• Description: Cancer

Biological Activity

• Description: Doxorubicin (Adriamycin) is an antibiotic agent that inhibits DNA topoisomerase II and induces DNA damage and apoptosis.
• In Vitro: Doxorubicin, an antibiotic anthracycline, is commonly considered to exert its anti-tumor activity at two fundamental levels, altering DNA and producing free radicals to trigger apoptosis of cancer cells through DNA damage. Doxorubicin can block the synthesis of DNA by intercalating into the DNA strand, and inhibits DNA topoisomerase II (TOP2). Doxorubicin is most effective when cells are rapidly proliferating and expressing high levels of TOP2. Additionally, Doxorubicin can trigger apoptosis by producing ceramide (which prompts apoptosis by activating p53 or other downstream pathways such as JNK), the degradation of Akt by serine threonine proteases, the mitochondrial release of cytochrome c, increased FasL (death receptor Fas/CD95 ligand) mRNA production, and a greater production of free radicals. ^[2] Pre-treatment with GSNO (nitrosoglutathione) suppresses the resistance in the doxorubicin-resistant breast cancer cell line MCF7/Dx, accompanied by enhanced protein glutathionylation and accumulation of doxorubicin in the nucleus. ^[3] Doxorubicin induced G2/M checkpoint arrest are attributed to elevated cyclin G2 (CycG2) expression and phospho-modification of proteins in the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) signaling pathways. ^[5] Doxorubicin inhibits AMP-activated protein kinase (AMPK), resulting in SIRT1 dysfunction, p53 accumulation, and increased cell death in mouse embryonic fibroblasts (MEFs) and cardiomyocytes, which can be further sensitized by pre-inhibition of AMPK. ^[6] Doxorubicin elicits a marked heat shock response, and that either inhibition or silencing of heat shock proteins enhance the Doxorubicin apoptotic effect in neuroblastoma cells. Nanomolar Doxorubicin treatment of neuroblastoma cells causes dose-dependent over-ubiquitination of a specific set of proteins in the absence of measurable inhibition of proteasome, and loss of activity of ubiquitinated enzymes such as lactate dehydrogenase and α-enolase, the protein ubiquination patterns of which is similar to those with proteasome inhibitor Bortezomib, indicating that Doxorubicin may also exert its effect by damaging proteins. ^[8]
• In Vivo: Although its use is limited by the chronic and acute toxic side effects it produces, Doxorubicin is essential in treating breast and oesophageal carcinomas, solid tumours in childhood, osteosarcomas, Kaposi’s sarcoma, soft tissue sarcomas, and Hodgkin and non-Hodgkin lymphomas. ^[2] In vivo, Doxorubicin in combination with adenoviral MnSOD (AdMnSOD) plus 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) has the greatest effect in decreasing the volumes of MB231 tumors and prolonging survival of mice. ^[1]
• Clinical Trials: A Phase III study of Doxorubicin alone vs. Doxorubicin in combination with TH-302 in subjects with locally advanced unresectable or metastatic soft tissue sarcoma is currently ongoing.

Combination Therapy

• Description: Doxorubicin in combination with sodium butyrate (an HDACi) potentiates apoptosis and synergistically reduces the viability of myeloma cells independent of p53 and caspase 3-7 activation, which is correlated with nuclear translocation of apoptosis-inducing factor and significantly increased activity of cytoplasmic cathepsin B. Doxorubicin in combination with clinically relevant concentration of butyrate or SAHA significantly reduces the survival of primary myeloma cells. ^[4] Flavopiridol potentiates doxorubicin efficacy in sarcoma cell lines. In vivo, Doxorubicin administered 1 hour prior to flavopiridol is more active than Doxorubicin alone. ^[7] A Phase III study of Doxorubicin and Bortezomib or Bortezomib monotherapy for the treatment of telapsed multiple myeloma is currently ongoing.

Protocol

• Protocol: Animal Study ^[1]
• Animal Models: Female athymic nude mice injected s.c. with MB231 cells
• Formulation: Dissolved in DMSO, and diluted in saline
• Doses: 3 mg/kg/day
• Administration: Delivered intratumorly

References

• References: [1] Sun W, et al. Cancer Res, 2009, 69(10), 4294-4300.
• References: [2] Granados-Principal S, et al. Food Chem Toxicol, 2010, 48(6), 1425-1438.
• References: [3] de Luca A, et al. Biochem J, 2011, 440(2), 175-183.
• References: [4] Cheriyath V, et al. Br J Cancer, 2011, 104(6), 957-967.
• References: [5] Zimmermann M, et al. J Biol Chem, 2012, 287(27), 22838-22853.
• References: [6] Wang S, et al. J Biol Chem, 2012, 287(11), 8001-8012.

Sigma Aldrich - 44583

Frequently Asked Questions
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Application
Do you have application information on this product that you would like to share?
Doxorubicin is used as an antitumour antibiotic, to induce apoptosis, and to induce cardiotoxicity in SK-N-MC cells 2,3.
Used to inhibit macromolecular biosynthsis.
Biochem/physiol Actions
Antitumour antibiotic. Effect of adriamycin® on heart mitochondrial DNA;4 Properties.5,6
Inhibitor of reverse transcriptase and RNA polymerase; immunosuppressive agent; intercalates in DNA.
Doxorubicin intercalates DNA and inhibits macromolecular biosynthesis. DNA replication is haulted due to the inhibition of topoisomerase II. It is an inhibitor of reverse transcriptase and RNA polymerase and is an immunosuppressive agent 1.
Legal Information
Adriamycin is a registered trademark of RDF Pharmacia & Upjohn S.P.A.
Protocols & Applications
Antibiotic Selector for application, solubility, solution stability, working concentration, and mode of action information

REFERENCES

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• Sun W, et al. Cancer Res, 2009, 69(10), 4294-4300.
• Granados-Principal S, et al. Food Chem Toxicol, 2010, 48(6), 1425-1438.
• de Luca A, et al. Biochem J, 2011, 440(2), 175-183.
• Cheriyath V, et al. Br J Cancer, 2011, 104(6), 957-967.
• Zimmermann M, et al. J Biol Chem, 2012, 287(27), 22838-22853.
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