Doxorubicinol | CAS#54193-28-1 |Doxorubicin Metabollite

MedKoo Cat#: 461446 | Name: Doxorubicinol

Description:

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

Doxorubicinol is the primary circulating metabolite of doxorubicin which may be used as an antineoplastic.

Chemical Structure

Doxorubicinol

CAS#54193-28-1 (free base)

Theoretical Analysis

MedKoo Cat#: 461446

Name: Doxorubicinol

CAS#: 54193-28-1 (free base)

Chemical Formula: C27H31NO11

Exact Mass: 545.1897

Molecular Weight: 545.54

Elemental Analysis: C, 59.45; H, 5.73; N, 2.57; O, 32.26

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Related CAS #

63950-05-0 (HCl) 54193-28-1 (free base)

Synonym

13-Dihydrodoxorubicin, Doxorubicinol; Adriamycinol; Antibiotic 27706RP, RP 27706; RP-27706; RP27706;

IUPAC/Chemical Name

(8S,10S)-10-(((2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-8-((S)-1,2-dihydroxyethyl)-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione

InChi Key

NKZRZOVSJNSBFR-FEMMEMONSA-N

InChi Code

InChI=1S/C27H31NO11/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-,16-,17-,22+,27-/m0/s1

SMILES Code

O=C1C2=C(O)C(C[C@@](O)([C@@H](O)CO)C[C@@H]3O[C@H]4C[C@H](N)[C@H](O)[C@H](C)O4)=C3C(O)=C2C(C5=C1C=CC=C5OC)=O

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

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

Shelf Life

>3 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

2934.99.03.00

More Info

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Doxorubicinol is the primary circulating metabolite of doxorubicin which may be used as an antineoplastic.

In vitro activity:

DoxOL (doxorubicinol) abolished the increase in RyR2 activity when luminal Ca2+ was increased from 0.1 to 1.5 mM. DoxOL binding to CSQ2 reduced both the Ca2+ binding capacity of CSQ2 (by 48%-58%) and its aggregation, and lowered CSQ2 association with the RyR2 complex by 67%-77%. Reference: Mol Pharmacol. 2017 Nov;92(5):576-587. https://pubmed.ncbi.nlm.nih.gov/28916620/

In vivo activity:

Doxorubicin markedly affected rat body growth, as well as several ECG parameters such as S alpha T, R alpha T, alpha TP and T-wave. Typical cardiac histological alterations were also induced by doxorubicin. In a similar way, doxorubicinol treatment was associated with a significant inhibition of rat body weight increase, and the appearance of ECG alterations as well as both macro- and microscopic signs of cardiac tissue damage. Overall results indicate that doxorubicinol induces a doxorubicin-like toxic syndrome mainly affecting the heart, although to a lower degree of severity than that caused by the parent drug. Reference: Eur J Cancer Clin Oncol. 1987 Jul;23(7):907-13. https://pubmed.ncbi.nlm.nih.gov/3665998/

Preparing Stock Solutions

The following data is based on the product molecular weight 545.54 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:

1. Hanna AD, Lam A, Thekkedam C, Willemse H, Dulhunty AF, Beard NA. The Anthracycline Metabolite Doxorubicinol Abolishes RyR2 Sensitivity to Physiological Changes in Luminal Ca2+ through an Interaction with Calsequestrin. Mol Pharmacol. 2017 Nov;92(5):576-587. doi: 10.1124/mol.117.108183. Epub 2017 Sep 15. PMID: 28916620. 2. Schaupp CM, White CC, Merrill GF, Kavanagh TJ. Metabolism of doxorubicin to the cardiotoxic metabolite doxorubicinol is increased in a mouse model of chronic glutathione deficiency: A potential role for carbonyl reductase 3. Chem Biol Interact. 2015 Jun 5;234:154-61. doi: 10.1016/j.cbi.2014.11.010. Epub 2014 Nov 21. PMID: 25446851; PMCID: PMC4414687. 3. Breysse DH, Boone RM, Long CM, Merrill ME, Schaupp CM, White CC, Kavanagh TJ, Schmidt EE, Merrill GF. Carbonyl Reductase 1 Plays a Significant Role in Converting Doxorubicin to Cardiotoxic Doxorubicinol in Mouse Liver, but the Majority of the Doxorubicinol-Forming Activity Remains Unidentified. Drug Metab Dispos. 2020 Mar;48(3):187-197. doi: 10.1124/dmd.119.089326. Epub 2020 Jan 18. PMID: 31955137; PMCID: PMC7011114. 4. Danesi R, del Tacca M, Bernardini C, Penco S. Exogenous doxorubicinol induces cardiotoxic effects in rats. Eur J Cancer Clin Oncol. 1987 Jul;23(7):907-13. doi: 10.1016/0277-5379(87)90334-8. PMID: 3665998.

In vitro protocol:

In vivo protocol:

1. Breysse DH, Boone RM, Long CM, Merrill ME, Schaupp CM, White CC, Kavanagh TJ, Schmidt EE, Merrill GF. Carbonyl Reductase 1 Plays a Significant Role in Converting Doxorubicin to Cardiotoxic Doxorubicinol in Mouse Liver, but the Majority of the Doxorubicinol-Forming Activity Remains Unidentified. Drug Metab Dispos. 2020 Mar;48(3):187-197. doi: 10.1124/dmd.119.089326. Epub 2020 Jan 18. PMID: 31955137; PMCID: PMC7011114. 2. Danesi R, del Tacca M, Bernardini C, Penco S. Exogenous doxorubicinol induces cardiotoxic effects in rats. Eur J Cancer Clin Oncol. 1987 Jul;23(7):907-13. doi: 10.1016/0277-5379(87)90334-8. PMID: 3665998.

1: Pérez-Blanco JS, Fernández de Gatta Mdel M, Hernández-Rivas JM, García Sánchez MJ, Sayalero Marinero ML, González López F. Validation and clinical evaluation of a UHPLC method with fluorescence detector for plasma quantification of doxorubicin and doxorubicinol in haematological patients. J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Apr 1;955-956:93-7. doi: 10.1016/j.jchromb.2014.02.034. Epub 2014 Feb 28. PubMed PMID: 24631816. 2: Schaupp CM, White CC, Merrill GF, Kavanagh TJ. Metabolism of doxorubicin to the cardiotoxic metabolite doxorubicinol is increased in a mouse model of chronic glutathione deficiency: A potential role for carbonyl reductase 3. Chem Biol Interact. 2015 Jun 5;234:154-61. doi: 10.1016/j.cbi.2014.11.010. Epub 2014 Nov 21. PubMed PMID: 25446851; PubMed Central PMCID: PMC4414687. 3: Pérez-Blanco JS, Santos-Buelga D, Fernández de Gatta MD, Hernández-Rivas JM, Martín A, García MJ. Population pharmacokinetics of doxorubicin and doxorubicinol in patients diagnosed with non-Hodgkin's lymphoma. Br J Clin Pharmacol. 2016 Dec;82(6):1517-1527. doi: 10.1111/bcp.13070. Epub 2016 Sep 6. PubMed PMID: 27447545; PubMed Central PMCID: PMC5099548. 4: Salvatorelli E, Menna P, Paz OG, Chello M, Covino E, Singer JW, Minotti G. The novel anthracenedione, pixantrone, lacks redox activity and inhibits doxorubicinol formation in human myocardium: insight to explain the cardiac safety of pixantrone in doxorubicin-treated patients. J Pharmacol Exp Ther. 2013 Feb;344(2):467-78. doi: 10.1124/jpet.112.200568. Epub 2012 Nov 28. PubMed PMID: 23192654. 5: Sottani C, Poggi G, Melchiorre F, Montagna B, Minoia C. Simultaneous measurement of doxorubicin and reduced metabolite doxorubicinol by UHPLC-MS/MS in human plasma of HCC patients treated with TACE. J Chromatogr B Analyt Technol Biomed Life Sci. 2013 Feb 1;915-916:71-8. doi: 10.1016/j.jchromb.2012.12.012. Epub 2012 Dec 22. PubMed PMID: 23337906. 6: Olson RD, Mushlin PS, Brenner DE, Fleischer S, Cusack BJ, Chang BK, Boucek RJ Jr. Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proc Natl Acad Sci U S A. 1988 May;85(10):3585-9. PubMed PMID: 2897122; PubMed Central PMCID: PMC280258. 7: Cusack BJ, Tesnohlidek DA, Loseke VL, Vestal RE, Brenner DE, Olson RD. Effect of phenytoin on the pharmacokinetics of doxorubicin and doxorubicinol in the rabbit. Cancer Chemother Pharmacol. 1988;22(4):294-8. PubMed PMID: 3168142. 8: Gilbert CM, Filippich LJ, McGeary RP, Charles BG. Toxicokinetics of the active doxorubicin metabolite, doxorubicinol, in sulphur-crested cockatoos (Cacatua galerita). Res Vet Sci. 2007 Aug;83(1):123-9. Epub 2007 Jan 2. PubMed PMID: 17197005. 9: Wang GX, Wang YX, Zhou XB, Korth M. Effects of doxorubicinol on excitation--contraction coupling in guinea pig ventricular myocytes. Eur J Pharmacol. 2001 Jul 6;423(2-3):99-107. PubMed PMID: 11448472. 10: Salvatorelli E, Menna P, Cascegna S, Liberi G, Calafiore AM, Gianni L, Minotti G. Paclitaxel and docetaxel stimulation of doxorubicinol formation in the human heart: implications for cardiotoxicity of doxorubicin-taxane chemotherapies. J Pharmacol Exp Ther. 2006 Jul;318(1):424-33. Epub 2006 Apr 13. PubMed PMID: 16614166. 11: Mushlin PS, Cusack BJ, Boucek RJ Jr, Andrejuk T, Li X, Olson RD. Time-related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function. Br J Pharmacol. 1993 Nov;110(3):975-82. PubMed PMID: 8298821; PubMed Central PMCID: PMC2175809. 12: Liu Y, Yang Y, Liu X, Jiang T. Quantification of pegylated liposomal doxorubicin and doxorubicinol in rat plasma by liquid chromatography/electrospray tandem mass spectroscopy: Application to preclinical pharmacokinetic studies. Talanta. 2008 Jan 15;74(4):887-95. doi: 10.1016/j.talanta.2007.07.022. Epub 2007 Jul 31. PubMed PMID: 18371724. 13: Cusack BJ, Young SP, Driskell J, Olson RD. Doxorubicin and doxorubicinol pharmacokinetics and tissue concentrations following bolus injection and continuous infusion of doxorubicin in the rabbit. Cancer Chemother Pharmacol. 1993;32(1):53-8. PubMed PMID: 8462124. 14: Callies S, de Alwis DP, Wright JG, Sandler A, Burgess M, Aarons L. A population pharmacokinetic model for doxorubicin and doxorubicinol in the presence of a novel MDR modulator, zosuquidar trihydrochloride (LY335979). Cancer Chemother Pharmacol. 2003 Feb;51(2):107-18. Epub 2003 Jan 10. PubMed PMID: 12647011. 15: Webster LK, Cosson EJ, Stokes KH, Millward MJ. Effect of the paclitaxel vehicle, Cremophor EL, on the pharmacokinetics of doxorubicin and doxorubicinol in mice. Br J Cancer. 1996 Feb;73(4):522-4. PubMed PMID: 8595168; PubMed Central PMCID: PMC2074445. 16: Nielson CP, Brenner D, Olson RD. Doxorubicin and doxorubicinol-induced alterations in human polymorphonuclear leukocyte oxygen metabolite generation. J Pharmacol Exp Ther. 1986 Jul;238(1):19-25. PubMed PMID: 3088258. 17: Jacquet JM, Bressolle F, Galtier M, Bourrier M, Donadio D, Jourdan J, Rossi JF. Doxorubicin and doxorubicinol: intra- and inter-individual variations of pharmacokinetic parameters. Cancer Chemother Pharmacol. 1990;27(3):219-25. PubMed PMID: 2265458. 18: Danesi R, del Tacca M, Bernardini C, Penco S. Exogenous doxorubicinol induces cardiotoxic effects in rats. Eur J Cancer Clin Oncol. 1987 Jul;23(7):907-13. PubMed PMID: 3665998. 19: de Bruijn P, Verweij J, Loos WJ, Kolker HJ, Planting AS, Nooter K, Stoter G, Sparreboom A. Determination of doxorubicin and doxorubicinol in plasma of cancer patients by high-performance liquid chromatography. Anal Biochem. 1999 Jan 15;266(2):216-21. PubMed PMID: 9888978. 20: Johansen PB, Jensen SE, Rasmussen SN, Dalmark M. 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