-Aldoxorubicin; Doxorubicin(6-maleimidocaproyl)hydrazone) Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C37H42N4O13 |
| Exact Mass | 750.275 |
| CAS # | 151038-96-9 |
| Related CAS # | Aldoxorubicin;1361644-26-9;MC-DOXHZN hydrochloride;480998-12-7 |
| PubChem CID | 9810709 |
| Appearance | Typically exists as solid at room temperature |
| LogP | 1.418 |
| Hydrogen Bond Donor Count | 7 |
| Hydrogen Bond Acceptor Count | 15 |
| Rotatable Bond Count | 12 |
| Heavy Atom Count | 54 |
| Complexity | 1510 |
| Defined Atom Stereocenter Count | 6 |
| SMILES | [H][C@@]1(O[C@H]2C[C@@](/C(CO)=N\NC(CCCCCN3C(C=CC3=O)=O)=O)(O)CC(C2=C4O)=C(O)C5=C4C(C6=C(OC)C=CC=C6C5=O)=O)O[C@@H](C)[C@@H](O)[C@@H](N)C1 |
| InChi Key | OBMJQRLIQQTJLR-USGQOSEYSA-N |
| InChi Code | InChI=1S/C37H42N4O13/c1-17-32(46)20(38)13-27(53-17)54-22-15-37(51,23(16-42)39-40-24(43)9-4-3-5-12-41-25(44)10-11-26(41)45)14-19-29(22)36(50)31-30(34(19)48)33(47)18-7-6-8-21(52-2)28(18)35(31)49/h6-8,10-11,17,20,22,27,32,42,46,48,50-51H,3-5,9,12-16,38H2,1-2H3,(H,40,43)/b39-23+/t17-,20-,22-,27-,32+,37-/m0/s1 |
| Chemical Name | N-[(E)-[1-[(2S,4S)-4-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1H-tetracen-2-yl]-2-hydroxyethylidene]amino]-6-(2,5-dioxopyrrol-1-yl)hexanamide |
| Synonyms | ALDOXORUBICIN; 1361644-26-9; INNO-206; DOXO-EMCH; Doxorubicin-EMCH; 151038-96-9; MC-Doxhzn; N-[(E)-[1-[(2S,4S)-4-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1H-tetracen-2-yl]-2-hydroxyethylidene]amino]-6-(2,5-dioxopyrrol-1-yl)hexanamide; |
| 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 | Topoisomerase II Daunorubicins/Doxorubicins |
| ln Vitro |
Aldoxorubicin, an antineoplastic agents, is an albumin-binding prodrug of doxorubicin. Aldoxorubicin is a 6-maleimidocaproyl hydrazone derivative prodrug of the anthracycline antibiotic doxorubicin (DOXO-EMCH) with antineoplastic activity. Following intravenous administration, aldoxorubicin binds selectively to the cysteine-34 position of albumin via its maleimide moiety. Doxorubicin is released from the albumin carrier after cleavage of the acid-sensitive hydrazone linker within the acidic environment of tumors and, once located intracellularly, intercalates DNA, inhibits DNA synthesis, and induces apoptosis. Albumin tends to accumulate in solid tumors as a result of high metabolic turnover, rapid angiogenesis, hypervasculature, and impaired lymphatic drainage. Because of passive accumulation within tumors, this agent may improve the therapeutic effects of doxorubicin while minimizing systemic toxicity. |
| ln Vivo | DOXO-EMCH a 6-maleimidocaproyl hydrazone derivative of doxorubicin, is an albumin binding prodrug which has entered clinical trials because of its superior antitumor and toxicological profile. In the present work, researchers examined the chronic cardiotoxicity of DOXO-EMCH in direct comparison with doxorubicin. Rats (11 weeks of age) were treated with intravenous doxorubicin (0.8 mg/kg weekly for 7 weeks), an equimolar dose of DOXO-EMCH (1.1 mg/kg), or with 3.3 mg/kg of DOXO-EMCH. Controls received saline. Animals were euthanized at 48th week. Rats exposed to doxorubicin had a severe clinical, and histopathological cardiomyopathy with depressed myocardial activity of cytochrome c-oxidase (COX, 26% of controls), reduced expression of the mtDNA-encoded COX II subunit, decreased mtDNA copy numbers (46% of controls), and high levels of malondialdehyde and superoxide (787% of controls). All parameters were highly correlated with myocardial damage. Both DOXO-EMCH groups did not differ from controls with regard to clinical symptomatology, mortality and mitochondrial enzymes, although the myocardia of the high-dose group had slightly increased histopathological abnormalities, depressed mtDNA copies (74% of controls) and elevated superoxide levels (347% of controls). Doxorubicin-exposed hearts and to a lesser extent the myocardia of both DOXO-EMCH groups contained mtDNA-deletions. In summary both DOXO-EMCH doses were superior over doxorubicin with respect to clinical and histopathological evidence of cardiomyopathy, myocardial COX-activity, COX II expression, mtDNA-content, mtDNA mutation loads and superoxide production in rats[2]. |
| Animal Protocol | Male Wistar rats were housed in a normal night–day rhythm under standard conditions of temperature, humidity and fed a normal rat chow. At 10 weeks of age, the rats received an intravenous port under anesthesia with Forene™. Based on the mortality in earlier investigations, the rats were divided into 4 experimental groups of different size: 9 animals served as controls (Group A) and received intravenous saline (300–700 μl). Group B (n = 15) received equivalent volumes of doxorubicin at a dose of 0.8 mg/kg, freshly dissolved in water from lyophilized powder. Group C, the DOXO-EMCH low-dose group (n = 10), received intravenous DOXO-EMCH, synthesized according to a published procedure and freshly reconstituted in sterile 10 mM sodium phosphate, 5 % D-(+)-glucose (pH 6.4) and at a dose equivalent to 0.8 mg/kg of free doxorubicin (1.1 mg/kg). Group D (n = 10) was injected with a higher dose of DOXO-EMCH (3.3 mg/kg), a dose that with respect to subacute mortality was equitoxic to 0.8 mg/kg of doxorubicin in a 4-cycle repeat dose study in rats. All animals received 7-weekly injections through the port, beginning at 11 weeks of age and were killed by cervical dislocation at 48 weeks of age, immediately before postmortem examination and organ collection. Heart weights were recorded. Left ventricle and apex were snap frozen and cryopreserved in liquid nitrogen until subsequent analysis. Aliquots were fixed in glutaraldehyde (3%) for subsequent electron microscopy.[3] |
| References |
[1]. Hydrazone, Amide, Carbamate, Macromolecular and Other Prodrugs of Doxorubicin. The Open Drug Delivery Journal, 2008, 2, 77-85. |
| Additional Infomation |
Aldoxorubicin, an antineoplastic agents, is an albumin-binding prodrug of doxorubicin. Aldoxorubicin is a 6-maleimidocaproyl hydrazone derivative prodrug of the anthracycline antibiotic doxorubicin (DOXO-EMCH) with antineoplastic activity. Following intravenous administration, aldoxorubicin binds selectively to the cysteine-34 position of albumin via its maleimide moiety. Doxorubicin is released from the albumin carrier after cleavage of the acid-sensitive hydrazone linker within the acidic environment of tumors and, once located intracellularly, intercalates DNA, inhibits DNA synthesis, and induces apoptosis. Albumin tends to accumulate in solid tumors as a result of high metabolic turnover, rapid angiogenesis, hypervasculature, and impaired lymphatic drainage. Because of passive accumulation within tumors, this agent may improve the therapeutic effects of doxorubicin while minimizing systemic toxicity. Drug Indication Investigated for use/treatment in solid tumors. Mechanism of Action INNO-206 is the (6-Maleimidocaproyl) hydrazone of doxorubicin. INNO-206 is a prodrug of doxorubicin that binds endogenous albumin after administration. The bound doxorubicin is released in the acidic environment of the tumor cell through cleavage of an acid sensitive linker. In preclinical models, INNO-206 was superior to doxorubicin with regard to antitumor efficacy and toxicity. |
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.) |