 Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C27H32CLNO11 |
| Molecular Weight | 582.00 |
| Exact Mass | 581.166 |
| Elemental Analysis | C, 55.72; H, 5.54; Cl, 6.09; N, 2.41; O, 30.24 |
| CAS # | 63950-05-0 |
| Related CAS # | Doxorubicinol;54193-28-1 |
| PubChem CID | 83970 |
| Appearance | Pink to red solid powder |
| Density | 1.61g/cm3 |
| Boiling Point | 828.7ºC at 760 mmHg |
| Melting Point | 188-192ºC |
| Flash Point | 455ºC |
| Index of Refraction | 1.716 |
| LogP | 1.295 |
| Hydrogen Bond Donor Count | 7 |
| Hydrogen Bond Acceptor Count | 12 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 39 |
| Complexity | 935 |
| Defined Atom Stereocenter Count | 7 |
| SMILES | Cl.OCC([C@]1(C[C@H](OC2CC(N)C(O)C(C)O2)C2C(=C3C(=O)C4C(=CC=CC=4C(=O)C3=C(O)C=2C1)OC)O)O)O |
| InChi Key | ORLHIGGRLIJIIM-PNOIAXSSSA-N |
| InChi Code | InChI=1S/C27H31NO11.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-,16-,17-,22+,27-;/m0./s1 |
| Chemical Name | (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-9-[(1S)-1,2-dihydroxyethyl]-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione;hydrochloride |
| Synonyms | Doxorubicinol hydrochloride; 63950-05-0; 13-Dihydroadriamycin; 13-Dihydroadriamycin hydrochloride; 9LVW1H75S7; (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-9-[(1S)-1,2-dihydroxyethyl]-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione;hydrochloride; UNII-9LVW1H75S7; NSC-268238; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | Doxorubicin metabolite; cardiac sarcoplasmic reticulum calcium pump |
| ln Vitro | The reduction of the doxorubicin side-chain carbonyl group (C13) to a secondary alcohol occurs in two electrons and is dependent on NADPH[1]. It has been demonstrated that the DNA binding activity of doxorubicinol hydrochloride is substantially lower than that of DOX. Furthermore, doxorubicin is primarily stored in the nucleus, whereas doxorubicinol hydrochloride is kept in the cytoplasm or lysosomes[1]. |
| ln Vivo | It has been discovered that nilotinib, which functions as an ABCB1 inhibitor in vivo in tumor-bearing mice, increases the build-up of doxorubicin and doxorubicinol hydrochloride in cancer tissues. This suggests that doxorubicinol hydrochloride's higher affinity for ABC transporters, which results in a lower intracellular concentration of the drug, may be linked to its lesser anticancer activity[1]. The terminal half-life and area under the plasma concentration-time curve of doxorubicin in mdr1a(-/-) mice are 1.6 and 1.2 times greater, respectively, compared to wild-type mice. The hearts of mdr1a(-/-) mice retain doxorubicin and its metabolite doxorubicinol hydrochloride for significantly longer[2]. |
| Enzyme Assay | Doxorubicin (former generic name, adriamycin), a highly effective anticancer drug, produces cardiotoxicity, which limits its therapeutic potential. The mechanism of this cardiotoxicity has remained elusive. Our data suggest that this toxicity could involve doxorubicinol, the primary circulating metabolite of doxorubicin. Doxorubicinol was markedly more potent than doxorubicin at compromising both systolic and diastolic cardiac function. Similarly, doxorubicinol was much more potent than doxorubicin at inhibiting the calcium pump of sarcoplasmic reticulum [ATP phosphohydrolase (Ca2+-transporting), EC 3.6.1.38], the Na+/K+ pump of sarcolemma [ATP phosphohydrolase (Na+/K+-transporting), EC 3.6.1.37], and the F0F1 proton pump of mitochondria [ATP phosphohydrolase (H+-transporting, EC 3.6.1.34]. Our finding that this highly toxic metabolite was produced by cardiac tissue exposed to doxorubicin suggests that doxorubicinol could accumulate in the heart and contribute significantly to the chronic cumulative cardiotoxicity of doxorubicin therapy. Our observation that doxorubicin was more potent than doxorubicinol in inhibiting tumor cell growth in vitro suggests that the cardiotoxicity of doxorubicin is dissociable from its anticancer activity[3]. |
| Cell Assay | The diastolic function of papillary muscles is inhibited by doxorubicin, which raises resting pressure [3]. At doses that markedly impair diastolic function, doxorubicin virtually completely abolishes calcium pump activity [3]. In canine and rabbit heart preparations, sarcoplasmic reticulum ATPase activity and sarcolemma Na+/K+-ATPase activity removal are reported [3]. The growth of PANC-1 cells is inhibited by doxorubicin at an IC50 of 35.4 μM, PD PaCa cells at 44.5 μM, and WD PaCa cells at 49.5 μM [3]. |
| Animal Protocol | To gain more insight into the pharmacological role of endogenous P-glycoprotein in the metabolism of the widely used substrate drug doxorubicin, we have studied the plasma pharmacokinetics, tissue distribution and excretion of this compound in mdr1a(-/-) and wild-type mice. Doxorubicin was administered as an i.v. bolus injection at a dose level of 5 mg kg(-1). Drug and metabolite concentrations were determined in plasma, tissues, urine and faeces by high-performance liquid chromatography. In comparison with wild-type mice, the terminal half-life and the area under the plasma concentration-time curve of doxorubicin in mdr1a(-/-) mice were 1.6- and 1.2-fold higher respectively. The retention of both doxorubicin and its metabolite doxorubicinol in the hearts of mdr1a(-/-) mice was substantially prolonged. In addition, a significantly increased drug accumulation was observed in the brain and the liver of mdr1a(-/-) mice. The relative accumulation in most other tissues was not or only slightly increased. The differences in cumulative faecal and urinary excretion of doxorubicin and metabolites between both types of mice were small. These experiments demonstrate that the absence of mdr1a P-glycoprotein only slightly alters the plasma pharmacokinetics of doxorubicin. Furthermore, the substantially prolonged presence of both doxorubicin and doxorubicinol in cardiac tissue of mdr1a(-/-) mice suggests that a blockade of endogenous P-glycoprotein in patients, for example by a reversal agent, may enhance the risk of cardiotoxicity upon administration of doxorubicin[2]. |
| References |
[1]. Metabolic carbonyl reduction of anthracyclines - role in cardiotoxicity and cancer resistance. Reducing enzymes as putative targets for novel cardioprotective and chemosensitizing agents. Invest New Drugs. 2017 Jun;35(3):375-385. [2]. Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr1a P-glycoprotein. Br J Cancer. 1999 Jan;79(1):108-13. [3]. Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proc Natl Acad Sci U S A. 1988 May;85(10):3585-9. |
| Additional Infomation |
Doxorubicinol is a member of the class of tetracenequinones that is the major metabolite of the anthracycline doxorubicin, a chemotherapeutic agent effective against a broad range of malignant neoplasms. It is thought to exhibit cardiotoxic properties. It has a role as a drug metabolite and a cardiotoxic agent. It is a member of p-quinones, an anthracycline antibiotic, a deoxy hexoside, an aminoglycoside, a member of tetracenequinones, a member of phenols, an aromatic ether and a polyol. It derives from a hydride of a tetracene. Doxorubicinol has been reported in Bos taurus with data available. |
Solubility Data
| Solubility (In Vitro) | May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples |
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7182 mL | 8.5911 mL | 17.1821 mL | |
| 5 mM | 0.3436 mL | 1.7182 mL | 3.4364 mL | |
| 10 mM | 0.1718 mL | 0.8591 mL | 1.7182 mL |