Aldoxorubicin HCl | CAS#480998-12-7

MedKoo Cat#: 201550 | Name: Aldoxorubicin HCl

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Aldoxorubicin, also known as INNO-206 and Doxo-EMCH, is the 6-maleimidocaproyl hydrazone derivative prodrug of the anthracycline antibiotic doxorubicin with antineoplastic activity. 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. NOTE: Current batch has ~90% purity by HPLC. The rest 10% is doxouribin HCl.

Chemical Structure

Aldoxorubicin HCl

CAS#480998-12-7 (HCl)

Theoretical Analysis

MedKoo Cat#: 201550

Name: Aldoxorubicin HCl

CAS#: 480998-12-7 (HCl)

Chemical Formula: C37H43ClN4O13

Exact Mass: 0.0000

Molecular Weight: 787.25

Elemental Analysis: C, 56.45; H, 5.51; Cl, 4.50; N, 7.12; O, 26.42

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
50mg	USD 250.00	Ready to ship
100mg	USD 450.00	Ready to ship
200mg	USD 750.00	Ready to ship
500mg	USD 1,250.00	Ready to ship
1g	USD 2,250.00	Ready to ship
2g	USD 3,850.00	Ready to ship

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Related CAS #

1361644-26-9 (free base) 480998-12-7 (HCl) 151038-96-9 (free base)

Synonym

DOXO-EMCH； EMCH-Doxo; EMCH-doxorubicin; INNO206; INNO-206; INNO 206; INNO-206 HCl; Aldoxorubicin. Doxorubicin prodrug.

IUPAC/Chemical Name

(E)-N'-(1-((2S,4S)-4-(((2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl)-2-hydroxyethylidene)-6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide hydrochloride

InChi Key

NGKHWQPYPXRQTM-UKFSEGPMSA-N

InChi Code

InChI=1S/C37H42N4O13.ClH/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);1H/b39-23+;/t17-,20-,22-,27-,32+,37-;/m0./s1

SMILES Code

O=C(CCCCCN1C(C=CC1=O)=O)N/N=C(CO)/[C@]2(O)CC3=C(C4=C(C(O)=C3[C@H](C2)O[C@@H]5O[C@H]([C@H]([C@H](C5)N)O)C)C(C6=C(C=CC=C6C4=O)OC)=O)O.[H]Cl

Appearance

Red solid powder

Purity

Current batch has 90% purity by HPLC. The rest 10% is doxouribin HCl.

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Related CAS# 480998-12-7 (HCl salt); 151038-96-9 (free base) INNO-206 - Mechanism of action: According to CytRx's website, the proposed mechanism of action is as the follow steps: (1) after administration, INNO-206 rapidly binds endogenous circulating albumin through the EMCH linker. (2) circulating albumin preferentially accumulates in tumors, bypassing uptake by other non-specific sites including heart, bone marrow and gastrointestinal tract; (3) once albumin-bound INNO-206 reaches the tumor, the acidic environment of the tumor causes cleavage of the acid sensitive linker; (4) free doxorubicin is released at the site of the tumor.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#M23D06K01

QC Data

View QC data: current batch, Lot#M23D06K01

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Aldoxorubicin (INNO-206) is an albumin-binding prodrug of Doxorubicin (DNA topoisomerase II inhibitor), which is released from albumin under acidic conditions.

In vitro activity:

Because INNO-206 shows that the highest level of releasing doxorubicin is at pH 5, the cytotoxicity of INNO-206 or doxorubicin was assessed in a concentration- and pH-dependent fashion in the 3 multiple myeloma cell lines RPMI8226, U266, and MM1S. First, drugs were prepared in pH 5 or 7 for 45 minutes before their addition to the cell culture. To compare equivalent concentrations of doxorubicin-bound INNO-206 to free doxorubicin, the INNO-206 concentrations were divided by 1.346 as this gives the amount of free doxorubicin contained within the INNO-206 compound. Cells were then exposed to increasing concentrations of INNO-206 from 0.27 to 2.16 μmol/L (free doxorubicin equivalent doses of 0.2–1.6 μmol/L) or doxorubicin (0.2–1.6 μmol/L) for 48 hours, and cell viability was determined with the MTS assay. A concentration- and pH-dependent decrease in viable RPMI8226 cells was observed after exposure to INNO-206 or doxorubicin (Fig. 1A). At pH 5, viable cells were essentially eliminated in cells cultured with INNO-206 at concentrations ≥0.54 μmol/L and doxorubicin was also effective but less so than INNO-206 (Fig. 1A). A similar concentration and pH-dependent inhibition of cell growth, as those observed earlier, was observed in the MM1S cell line after exposure to INNO-206 or doxorubicin (Fig. 1B). As the concentration was increased and pH was decreased, from pH 7 to 5, the percentage of viable MM1S cells within the INNO-206 group dramatically decreased, in contrast to what occurred with doxorubicin. In fact, the anti–multiple myeloma effects of doxorubicin at 0.4 and 0.8 μmol/L were less at pH 5 than 7. The diminishing anti–multiple myeloma effects of doxorubicin in an acidic environment were also observed in the U266 cell line (Fig. 1C), in contrast to INNO-206 where increased anti–multiple myeloma effects were observed at the lower pH. Because the data above was generated from drugs incubated at physiologic pH and at pH 5, the effect of an acidic pH alone on multiple myeloma cell lines was also tested. Exposure of multiple myeloma cells to pH 5 only resulted in a minimal reduction in viable cells compared to those cultured at pH 7. A representative example from all 3 cell lines tested is shown in Fig. 1D. Reference: Clin Cancer Res. 2012 Jul 15;18(14):3856-67. http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=22619306

In vivo activity:

Mice bearing the LAGκ-1A tumor receiving INNO-206 once weekly via i.v. injection at 10.8 mg/kg (equivalent to 8.0 mg/kg of doxorubicin) showed significantly smaller tumor volumes and IgG levels on days 28 (tumor volumes: P = 0.0152; hIgG: P = 0.0019), 35 (tumor volumes: P = 0.0051; hIgG: P = 0.0006) and 42 (tumor volumes: P = 0.0036; hIgG: P = 0.0113) compared with vehicle—treated mice (Fig. 3A and B). This INNO-206 treatment regimen was well tolerated with 90% of mice surviving until the termination of the study (day 42). Reference: Clin Cancer Res. 2012 Jul 15;18(14):3856-67. http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=22619306

	Solvent	mg/mL	mM
Solubility
	DMSO	6.0	20.30

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 787.25 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

In vitro protocol:

In vivo protocol:

1. Sanchez E, Li M, Wang C, Nichols CM, Li J, Chen H, Berenson JR. Anti-myeloma effects of the novel anthracycline derivative INNO-206. Clin Cancer Res. 2012 Jul 15;18(14):3856-67. doi: 10.1158/1078-0432.CCR-11-3130. Epub 2012 May 22. PMID: 22619306. 2. Graeser R, Esser N, Unger H, Fichtner I, Zhu A, Unger C, Kratz F. INNO-206, the (6-maleimidocaproyl hydrazone derivative of doxorubicin), shows superior antitumor efficacy compared to doxorubicin in different tumor xenograft models and in an orthotopic pancreas carcinoma model. Invest New Drugs. 2010 Feb;28(1):14-9. doi: 10.1007/s10637-008-9208-2. Epub 2009 Jan 8. PMID: 19148580.

1: Sheng Y, Xu J, You Y, Xu F, Chen Y. Acid-Sensitive Peptide-Conjugated Doxorubicin Mediates the Lysosomal Pathway of Apoptosis and Reverses Drug Resistance in Breast Cancer. Mol Pharm. 2015 Jul 6;12(7):2217-28. doi: 10.1021/mp500386y. Epub 2015 Jun 2. PubMed PMID: 26035464. 2: Mita MM, Natale RB, Wolin EM, Laabs B, Dinh H, Wieland S, Levitt DJ, Mita AC. Pharmacokinetic study of aldoxorubicin in patients with solid tumors. Invest New Drugs. 2015 Apr;33(2):341-8. doi: 10.1007/s10637-014-0183-5. Epub 2014 Nov 12. PubMed PMID: 25388939; PubMed Central PMCID: PMC4387275. 3: Marrero L, Wyczechowska D, Musto AE, Wilk A, Vashistha H, Zapata A, Walker C, Velasco-Gonzalez C, Parsons C, Wieland S, Levitt D, Reiss K, Prakash O. Therapeutic efficacy of aldoxorubicin in an intracranial xenograft mouse model of human glioblastoma. Neoplasia. 2014 Oct 23;16(10):874-82. doi: 10.1016/j.neo.2014.08.015. eCollection 2014 Oct. PubMed PMID: 25379024; PubMed Central PMCID: PMC4212249. 4: Kratz F, Azab S, Zeisig R, Fichtner I, Warnecke A. Evaluation of combination therapy schedules of doxorubicin and an acid-sensitive albumin-binding prodrug of doxorubicin in the MIA PaCa-2 pancreatic xenograft model. Int J Pharm. 2013 Jan 30;441(1-2):499-506. doi: 10.1016/j.ijpharm.2012.11.003. Epub 2012 Nov 10. PubMed PMID: 23149257. 5: Walker L, Perkins E, Kratz F, Raucher D. 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. doi: 10.1016/j.ijpharm.2012.07.043. Epub 2012 Jul 28. PubMed PMID: 22850291; PubMed Central PMCID: PMC3465682. 6: Kratz F, Warnecke A. Finding the optimal balance: challenges of improving conventional cancer chemotherapy using suitable combinations with nano-sized drug delivery systems. J Control Release. 2012 Dec 10;164(2):221-35. doi: 10.1016/j.jconrel.2012.05.045. Epub 2012 Jun 13. Review. PubMed PMID: 22705248. 7: Sanchez E, Li M, Wang C, Nichols CM, Li J, Chen H, Berenson JR. Anti-myeloma effects of the novel anthracycline derivative INNO-206. Clin Cancer Res. 2012 Jul 15;18(14):3856-67. doi: 10.1158/1078-0432.CCR-11-3130. Epub 2012 May 22. PubMed PMID: 22619306. 8: Kratz F, Elsadek B. Clinical impact of serum proteins on drug delivery. J Control Release. 2012 Jul 20;161(2):429-45. doi: 10.1016/j.jconrel.2011.11.028. Epub 2011 Dec 1. Review. PubMed PMID: 22155554. 9: Elsadek B, Kratz F. Impact of albumin on drug delivery--new applications on the horizon. J Control Release. 2012 Jan 10;157(1):4-28. doi: 10.1016/j.jconrel.2011.09.069. Epub 2011 Sep 16. Review. PubMed PMID: 21959118. 10: Kratz F, Fichtner I, Graeser R. Combination therapy with the albumin-binding prodrug of doxorubicin (INNO-206) and doxorubicin achieves complete remissions and improves tolerability in an ovarian A2780 xenograft model. Invest New Drugs. 2012 Aug;30(4):1743-9. doi: 10.1007/s10637-011-9686-5. Epub 2011 May 18. PubMed PMID: 21590366. 11: Boga C, Fiume L, Baglioni M, Bertucci C, Farina C, Kratz F, Manerba M, Naldi M, Di Stefano G. Characterisation of the conjugate of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin with lactosaminated human albumin by 13C NMR spectroscopy. Eur J Pharm Sci. 2009 Oct 8;38(3):262-9. doi: 10.1016/j.ejps.2009.08.001. Epub 2009 Aug 18. PubMed PMID: 19695327. 12: Graeser R, Esser N, Unger H, Fichtner I, Zhu A, Unger C, Kratz F. INNO-206, the (6-maleimidocaproyl hydrazone derivative of doxorubicin), shows superior antitumor efficacy compared to doxorubicin in different tumor xenograft models and in an orthotopic pancreas carcinoma model. Invest New Drugs. 2010 Feb;28(1):14-9. doi: 10.1007/s10637-008-9208-2. Epub 2009 Jan 8. PubMed PMID: 19148580. 13: Kratz F. Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control Release. 2008 Dec 18;132(3):171-83. doi: 10.1016/j.jconrel.2008.05.010. Epub 2008 May 17. Review. PubMed PMID: 18582981. 14: Unger C, Häring B, Medinger M, Drevs J, Steinbild S, Kratz F, Mross K. Phase I and pharmacokinetic study of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin. Clin Cancer Res. 2007 Aug 15;13(16):4858-66. PubMed PMID: 17699865. 15: Lebrecht D, Walker UA. Role of mtDNA lesions in anthracycline cardiotoxicity. Cardiovasc Toxicol. 2007;7(2):108-13. Review. PubMed PMID: 17652814. 16: Kratz F. DOXO-EMCH (INNO-206): the first albumin-binding prodrug of doxorubicin to enter clinical trials. Expert Opin Investig Drugs. 2007 Jun;16(6):855-66. Review. PubMed PMID: 17501697. 17: Kratz F, Ehling G, Kauffmann HM, Unger C. 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. Hum Exp Toxicol. 2007 Jan;26(1):19-35. PubMed PMID: 17334177. 18: Lebrecht D, Geist A, Ketelsen UP, Haberstroh J, Setzer B, Kratz F, Walker UA. 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. PubMed PMID: 17131338. 19: Di Stefano G, Lanza M, Kratz F, Merina L, Fiume L. A novel method for coupling doxorubicin to lactosaminated human albumin by an acid sensitive hydrazone bond: synthesis, characterization and preliminary biological properties of the conjugate. Eur J Pharm Sci. 2004 Dec;23(4-5):393-7. PubMed PMID: 15567293.

1. Zhou J, Meng N, Lu L, Lu J, Wu S, Ding Y, Wu S, Bao Y, Xu Q, Chen R, Wang J, Xie C, Wu J, Lu W. A novel peptide-drug conjugate for glioma-targeted drug delivery. J Control Release. 2024 May;369:722-733. doi: 10.1016/j.jconrel.2024.04.011. Epub 2024 Apr 13. PMID: 38583575. 2. Zhao Y, Fay F, Hak S, Manuel Perez-Aguilar J, Sanchez-Gaytan BL, Goode B, Duivenvoorden R, de Lange Davies C, Bjørkøy A, Weinstein H, Fayad ZA, Pérez-Medina C, Mulder WJ. Augmenting drug-carrier compatibility improves tumour nanotherapy efficacy. Nat Commun. 2016 Apr 13;7:11221. doi: 10.1038/ncomms11221. PMID: 27071376; PMCID: PMC4833858. 3. Bellat V, Michel AO, Thomas C, Stokol T, Choi BB, Law B. A Urinary Drug-Disposing Approach as an Alternative to Intravesical Chemotherapy for Treating Nonmuscle Invasive Bladder Cancer. Cancer Res. 2022 Apr 1;82(7):1409-1422. doi: 10.1158/0008-5472.CAN-21-2897. PMID: 35039320; PMCID: PMC8983499. 4. P Yousefpour: Genetically Encoded Albumin Binding Drug Delivery Systems- 2018 - dukespace.lib.duke.edu, Duke University. https://dukespace.lib.duke.edu/bitstreams/bf5d2f39-189e-46d5-815b-4c9b486a43ed/download 5. Targeted Combination Therapy of Triple-Negative Breast Cancer, K Bhise - 2021 - search.proquest.com https://search.proquest.com/openview/fa3ef9634fdafa399f56f65dd448bef3/1?pq-origsite=gscholar&cbl=18750&diss=y