DOXO-EMCH

Prodrug of doxorubicin CAS# 151038-96-9

DOXO-EMCH

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Chemical structure

DOXO-EMCH

3D structure

Chemical Properties of DOXO-EMCH

Cas No. 151038-96-9 SDF Download SDF
PubChem ID 9576002 Appearance Powder
Formula C37H42N4O13 M.Wt 750.75
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Doxorubicin-EMCH
Solubility DMSO
Chemical Name N-[(E)-[1-[4-(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
SMILES CC1C(C(CC(O1)OC2CC(CC3=C(C4=C(C(=C23)O)C(=O)C5=C(C4=O)C=CC=C5OC)O)(C(=NNC(=O)CCCCCN6C(=O)C=CC6=O)CO)O)N)O
Standard InChIKey OBMJQRLIQQTJLR-JRZNSJKLSA-N
Standard InChI 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+
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of DOXO-EMCH

DescriptionDOXO-EMCH is a 6-maleimidocaproyl hydrazone derivative of Doxorubicin, is an albumin binding prodrug.In Vitro:DOXO-EMCH is an an acid-sensitive prodrug of Doxorubicin that binds rapidly and selectively to the cysteine-34 position of circulating albumin[1].In Vivo:DOXO-EMCH is a 6-maleimidocaproyl hydrazone derivative of Doxorubicin. DOXO-EMCH unlike its free Doxorubicin parent, achieves complete remissions in a murine renal cell carcinoma model and in 2 breast carcinoma xenograft models. Moreover, DOXO-EMCH is also superior to Doxorubicin with regard to drug toxicity in mice, rats and dogs, and exhibits a good safety profile[2].

References:
[1]. Walker L, et al. Cell penetrating peptides fused to a thermally targeted biopolymer drug carrier improve the delivery and antitumor efficacy of an acid-sensitive doxorubicin derivative. Int J Pharm. 2012 Oct 15;436(1-2):825-32. [2]. Lebrecht D, et al. The 6-maleimidocaproyl hydrazone derivative of doxorubicin (DOXO-EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage. Int J Cancer. 2007 Feb 15;120(4):927-34. [3]. Liu L, et al. Albumin Binding Domain Fusing R/K-X-X-R/K Sequence for Enhancing Tumor Delivery of Doxorubicin. Mol Pharm. 2017 Nov 6;14(11):3739-3749.

Protocol

Animal Administration [2]
Rats[2] Male Wistar rats are 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 receive an intravenous port under anesthesia. Based on the mortality in earlier investigations, the rats are 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) receive 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), receive intravenous DOXO-EMCH, 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) is injected with a higher dose of DOXO-EMCH (3.3 mg/kg), a dose that with respect to subacute mortality is equitoxic to 0.8 mg/kg of Doxorubicin in a 4-cycle repeat dose study in rats. All animals receive 7-weekly injections through the port, beginning at 11 weeks of age and are killed by cervical dislocation at 48 weeks of age, immediately before postmortem examination and organ collection. Heart weights are recorded. Left ventricle and apex are snap frozen and cryopreserved in liquid nitrogen until subsequent analysis. Aliquots are fixed in glutaraldehyde (3%) for subsequent electron microscopy.

References:
[1]. Walker L, et al. Cell penetrating peptides fused to a thermally targeted biopolymer drug carrier improve the delivery and antitumor efficacy of an acid-sensitive doxorubicin derivative. Int J Pharm. 2012 Oct 15;436(1-2):825-32. [2]. Lebrecht D, et al. The 6-maleimidocaproyl hydrazone derivative of doxorubicin (DOXO-EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage. Int J Cancer. 2007 Feb 15;120(4):927-34. [3]. Liu L, et al. Albumin Binding Domain Fusing R/K-X-X-R/K Sequence for Enhancing Tumor Delivery of Doxorubicin. Mol Pharm. 2017 Nov 6;14(11):3739-3749.

DOXO-EMCH Dilution Calculator

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DOXO-EMCH Molarity Calculator

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Preparing Stock Solutions of DOXO-EMCH

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.332 mL 6.66 mL 13.32 mL 26.64 mL 33.3 mL
5 mM 0.2664 mL 1.332 mL 2.664 mL 5.328 mL 6.66 mL
10 mM 0.1332 mL 0.666 mL 1.332 mL 2.664 mL 3.33 mL
50 mM 0.0266 mL 0.1332 mL 0.2664 mL 0.5328 mL 0.666 mL
100 mM 0.0133 mL 0.0666 mL 0.1332 mL 0.2664 mL 0.333 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on DOXO-EMCH

DOXO-EMCH (151038-96-9) is defined as Double bond geometry unknown, also can be called as INNO-206 (1361644-26-9) with Double bond geometry (2E). INNO-206 (Aldoxorubicin) is the 6-maleimidocaproyl hydrazone derivative prodrug of the anthracycline antibiotic doxorubicin (DOXO-EMCH) with antineoplastic activity. Following intravenous administration, doxorubicin prodrug INNO-206 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, hyervasculature, and impaired lymphatic drainage. Because of passive accumulation within tumors, this agent may improve the therapeutic effects of doxorubicin while minimizing systemic toxicity. In a phase I study, INNO-206 showed a good safety profile at doses up to 260 mg/m2 doxorubicin equivalents. Although not the primary end point of the phase I study, INNO-206 was able to induce tumor regressions in breast cancer, small cell lung cancer and sarcoma.

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References on DOXO-EMCH

The 6-maleimidocaproyl hydrazone derivative of doxorubicin (DOXO-EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage.[Pubmed:17131338]

Int J Cancer. 2007 Feb 15;120(4):927-34.

Doxorubicin causes a chronic cardiomyopathy in which genetic and functional lesions of mitochondria accumulate in the long-term and explain in part the delayed onset of heart dysfunction. 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, we 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.

Acute and repeat-dose toxicity studies of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH), an albumin-binding prodrug of the anticancer agent doxorubicin.[Pubmed:17334177]

Hum Exp Toxicol. 2007 Jan;26(1):19-35.

The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that demonstrates superior antitumor efficacy in murine tumor models, and has been evaluated in a phase I study. In order to establish the toxicity profile of this prodrug, acute and repeat-dose toxicity studies were performed with DOXO-EMCH in CD1-mice, Sprague-Dawley rats and Beagle dogs. Although the objective of the acute toxicity studies was not the determination of LD50 values, the LD50 of DOXO-EMCH was >60 mg/kg doxorubicin equivalents in both male and female mice (the LD50 of doxorubicin in CD-1 mice is -12 mg/kg). In Sprague-Dawley rats, the LD50 was 23.4 and 45.9 mg/kg doxorubicin equivalents for males and females, respectively. For comparison, the LD50 of doxorubicin in Sprague-Dawley rats is -10.5 mg/kg. The major clinical sign noted following intravenous administration of DOXO-EMCH in mice and rats was a dose-dependent peripheral neuropathy which, in general, developed as a delayed toxicity 1-3 weeks after application. The observed neurotoxicity has been well documented for Sprague-Dawley rats treated with doxorubicin at a dose of 5 and 10 mg/kg. In Beagle dogs, LD10 was not reached for DOXO-EMCH at 4.5 mg/kg doxorubicin equivalents. A four-cycle intravenous study with DOXO-EMCH at dose levels of 4 x 2.5, 5.0 or 7.5 mg/kg doxorubicin equivalents in rats revealed approximately three-fold less side effects on the hemolymphoreticular system when compared to 4 x 2.5 mg/kg doxorubicin dose, whereas effects on the testes/oligospermia seem to be comparable between both drugs at equitoxic dose. A No Observable Adverse Effect Level (NOAEL) for DOXO-EMCH of 4 x 2.5 mg/kg doxorubicin equivalents was established in this study. This dose is equivalent to the maximum tolerated dose (MTD) of doxorubicin in rats. In a two-cycle study over a period of 6 weeks in Beagle dogs (intravenous administration of DOXO-EMCH at dose levels of 1.5, 3.0 or 4.5 mg/kg doxorubicin equivalents), dose-related systemic histamine-like reactions within the first 3 hours after injection were noted in all treated groups. Only transient and temporary effects on hematology, urinary function, as well as on histopathology in mid- and/or high-dose animals, were observed. The low dose of 2 x 1.5 mg/kg was considered to be the NOAEL in this study, which is equivalent to twice the MTD o f doxorubicin i nBeagle dogs. In summary, the toxicity studies with DOXO-EMCH in mice, rats or dogs have not identified any other special toxicity when compared to the toxicity data for doxorubicin. Preclinical tolerance of DOXO-EMCH was higher in mice, rats and dogs compared to doxorubicin. A dose of 20 mg/m2 doxorubicin equivalents was recommended as the starting dose for a phase I study with DOXO-EMCH.

DOXO-EMCH (INNO-206): the first albumin-binding prodrug of doxorubicin to enter clinical trials.[Pubmed:17501697]

Expert Opin Investig Drugs. 2007 Jun;16(6):855-66.

The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that demonstrates superior antitumor efficacy in murine tumor models and a favorable toxicity profile in mice, rats and dogs, including significantly reduced cardiotoxicity. After intravenous administration, DOXO-EMCH binds rapidly to the Cys-34 position of circulating albumin and accumulates in solid tumors due to passive targeting. In a clinical Phase I study, the dose of doxorubicin could be increased by a factor of 4.5-340 mg/m(2) when 75 mg/m(2) of free doxorubicin is considered to be the dose that can be administered as a single agent concomitant with the typical spectrum of side effects (i.e., myelotoxicity and mucositis). DOXO-EMCH was able to induce tumor regressions in anthracycline-sensitive tumors (i.e., breast cancer, small cell lung cancer and sarcoma). Phase II studies will be initiated at the beginning of 2007.

Description

DOXO-EMCH is a 6-maleimidocaproyl hydrazone derivative of Doxorubicin, is an albumin binding prodrug.

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