Description
Doxorubicin is an anthracycline antibiotic produced in Str. peucetius var. caesinus. Doxorubicin has anti-Gram-positive bacteria activity and has a broad anti-tumor spectrum. Doxorubicin is an antibiotic agent that inhibits DNA topoisomerase II and induces DNA damage and apoptosis.
Synonyms
(8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxohexopyranosyl)oxy]-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione; Adriamycin; Doxil; Adriablastin; Doxorubicine; Adriblastina; 14-Hydroxydaunomycin; 14-Hydroxydaunorubicine; Caelyx; Hydroxydaunorubicin; NSC-759155; 5,12-Naphthacenedione, 10-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, (8S-cis)-; NSC-123127; (1S,3S)-3,5,12-trihydroxy-3-(hydroxyacetyl)-10-(methyloxy)-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranoside; Epirubicin EP Impurity C
IUPAC Name
(7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione
Canonical SMILES
CC1C(C(CC(O1)OC2CC(CC3=C2C(=C4C(=C3O)C(=O)C5=C(C4=O)C(=CC=C5)OC)O)(C(=O)CO)O)N)O
InChI
InChI=1S/C27H29NO11/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/t10-,13-,15-,17-,22+,27-/m0/s1
InChIKey
AOJJSUZBOXZQNB-TZSSRYMLSA-N
Solubility
Soluble in DMF, DMSO, Ethanol, Methanol, Water (Poorly)
Index Of Refraction
1.709
Optical Rotation
Specific optical rotation: +248 deg at 20 °C/D (0.1% in methanol)
Vapor Pressure
9.64E-28mmHg at 25°C
UV Spectra
Max absorption (methanol at 56 °C): 290 nm (epsilon = 145, 1%, 1 cm); 477 nm (epsilon = 225, 1%, 1 cm); 495 nm (epsilon = 223, 1%, 1 cm); 530 nm (epsilon = 124, 1%, 1 cm); 233 nm (epsilon = 658, 1%, 1 cm); 253 nm (epsilon = 440, 1%, 1 cm)
Mechanism Of Action
Doxorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action: Doxorubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes.
Pharmacology
Doxorubicin is an antineoplastic in the anthracycline class. General properties of drugs in this class include: interaction with DNA in a variety of different ways including intercalation (squeezing between the base pairs), DNA strand breakage and inhibition with the enzyme topoisomerase II. Most of these compounds have been isolated from natural sources and antibiotics. However, they lack the specificity of the antimicrobial antibiotics and thus produce significant toxicity. The anthracyclines are among the most important antitumor drugs available. Doxorubicin is widely used for the treatment of several solid tumors while daunorubicin and idarubicin are used exclusively for the treatment of leukemia. Doxorubicin may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA. Doxorubicin possesses an antitumor effect against a wide spectrum of tumors, either grafted or spontaneous. The anthracyclines are cell cycle-nonspecific.
Toxicity (LD50)
LD50=21800 ug/kg (rat, subcutaneous).
In Vitro
Peritoneal macrophages from BD IX rats collected 24 hr after an i.p. injection of Adriamycin (10 mg/kg) were cytotoxic to syngeneic cancer cells in culture. In contrast, incubation in vitro in Adriamycin solutions did not evoke tumoricidal activity in peritoneal macrophages, whatever the incubation time (from 1 to 24 hr) and the Adriamycin concentration (from 1 ng to 100 micrograms/ml).
In Vivo
Macrophages incubated with Adriamycin in vitro accumulated the drug in their nuclei, whereas macrophages from animals receiving Adriamycin in vivo accumulated it is cytoplasmic vacuoles. Early observation of peritoneal cells after in vivo exposure to Adriamycin shows that Adriamycin is concentrated in mast cell granules which are released and then phagocytosed by peritoneal macrophages. Adriamycin fluorescence appears in nuclei of cancer cells incubated with in vivo-labeled macrophages, suggesting that macrophages can directly transfer the drug into cancer cells and therefore play a role in the Adriamycin antitumor effect.
Clinical Trial Information
| NCT Number | Condition Or Disease | Phase | Start Date | Sponsor | Status |
|---|
| NCT03023124 | Solitary Fibrous Tumors | Phase 2 | 2021-11-01 | Italian Sarcoma Group | Recruiting |
| NCT01404936 | Lymphoma | Phase 2 | 2013-02-01 | M.D. Anderson Cancer Center | Completed |
| NCT00107094 | Breast Cancer | Phase 1 | 2007-07-20 | Celgene Corporation | Completed |
| NCT03505164 | Doxorubicin Adverse Reaction | | 2021-04-27 | Rush University Medical Center | Completed |
| NCT03027063 | Breast Cancer Female | Not Applicable | 2021-01-05 | Johns Hopkins University | Completed |
Application
ADCs Cytotoxin
Source
Streptomyces peucetius
Appearance
Orange to Red Powder
Shelf Life
Neutral aq soln are stable at room temp
Shipping
-20°C (International: -20°C)
Pictograms
Irritant; Health Hazard
Boiling Point
810.3±65.0°C at 760 mmHg
Current Developer
Janssen Pharmaceutical K.K.
Assay
Dispense 160 μL cell suspension (3×10 4 cells/mL) into three 96-well U-bottom microplates and incubate for 24 h at 37 °C, 5% CO2 in a completely humidified atmosphere. In plate 1, add doxorubicin (20 μL; Final concentration, 0.1-2 μM) and simvastatin (20 μL; Final concentration, 0.25-2 μM) to a final volume of 200 μL and incubate for another 72 h. Then, add serial dilutions of other drugs (40 μL) and replenish the medium to a final volume of 200 μL and incubate for 48 h. Doxorubicin and simvastatin are used as positive controls alone (40 μL per well), and solvent-only cells are considered negative controls. To assess cell survival, add 20 μL of TTT solution (5 mg/mL in PBS) to each well and incubate for 3 h. The medium is then replaced with 150 μLDMSO and complete dissolution of the crystals is achieved by repeating the pipetting solution. The absorbance is then determined at 540 nm by ELISA plate reader. Determine the concentration of each drug in 4 or 8 wells and repeat 3 times. The cytotoxic/cytostatic effect of doxorubicin is expressed as relative survival (% control) and calculated.
