Valrubicin
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MedKoo CAT#: 100910

CAS#: 56124-62-0

Description: Valrubicin is a semisynthetic derivative of the antineoplastic anthracycline antibiotic doxorubicin. With a mechanism of action that appears to differ from doxorubicin, valrubicin is converted intracytoplasmically into N-trifluoroacetyladriamycin, which interacts with topoisomerase II, stabilizing the complex between the enzyme and DNA; consequently, DNA replication and repair and RNA and protein synthesis are inhibited and the cell cycle is arrested in the G2 phase. In addition, this agent accumulates in the cell cytoplasm where it inhibits protein kinase C (PKC). Valrubicin is less cardiotoxic than doxorubicin when administered systemically; applied topically, this agent shows excellent tissue penetration.


Chemical Structure

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Valrubicin
CAS# 56124-62-0

Theoretical Analysis

MedKoo Cat#: 100910
Name: Valrubicin
CAS#: 56124-62-0
Chemical Formula: C34H36F3NO13
Exact Mass: 723.21387
Molecular Weight: 723.64
Elemental Analysis: C, 56.43; H, 5.01; F, 7.88; N, 1.94; O, 28.74

Price and Availability

Size Price Availability Quantity
10.0mg USD 250.0 Ready to ship
25.0mg USD 350.0 Ready to ship
50.0mg USD 650.0 Ready to ship
100.0mg USD 1150.0 Ready to ship
200.0mg USD 1750.0 Ready to ship
500.0mg USD 2950.0 Ready to ship
1.0g USD 3950.0 2 weeks
2.0g USD 5650.0 2 weeks
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Synonym: Valrubicin, Valstar, Valtaxin, AD 32, AD32, AD-32

IUPAC/Chemical Name: 2-oxo-2-((2S,4S)-2,5,12-trihydroxy-4-(((2S,4S,5S,6S)-5-hydroxy-6-methyl-4-(2,2,2-trifluoroacetamido)tetrahydro-2H-pyran-2-yl)oxy)-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl)ethyl pentanoate

InChi Key: ZOCKGBMQLCSHFP-PIXAVGEUSA-N

InChi Code: InChI=1S/C34H36F3NO13/c1-4-5-9-21(40)49-13-20(39)33(47)11-16-24(19(12-33)51-22-10-17(27(41)14(2)50-22)38-32(46)34(35,36)37)31(45)26-25(29(16)43)28(42)15-7-6-8-18(48-3)23(15)30(26)44/h6-8,14,17,19,22,27,41,43,45,47H,4-5,9-13H2,1-3H3,(H,38,46)/t14-,17-,19-,22+,27+,33-/m0/s1

SMILES Code: CCCCC(OCC([C@@]1(O)C[C@H](O[C@@H]2C[C@H](NC(C(F)(F)F)=O)[C@H](O)[C@H](C)O2)C3=C(O)C4=C(C(C5=CC=CC(OC)=C5C4=O)=O)C(O)=C3C1)=O)=O

Appearance: Red 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, 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

Biological target: Valrubicin inhibits TPA- and PDBu-induced PKC activation with IC50s of 0.85 and 1.25 μM, respectively.
In vitro activity: Valrubicin's mode of action in keratinocytes was investigated by studying its possible effect on PKCα activation. PKCα's characteristic to translocate from the cytoplasm to the cellular membrane when activated was assessed by measuring the amount of PKCα in the soluble and membrane-bound protein fractions isolated from valrubicin stimulated keratinocytes and by visualizing PKCα in stimulated cells over time. Downstream signaling was investigated by measuring the amount of phosphorylated Myristoylated Alanine-rich C-kinase substrate (MARCKS) and extracellular signal-regulated kinases (ERK) 1/2 of valrubicin-stimulated keratinocytes. The results indicated that valrubicin activates PKCα in vitro as shown by PKCα's translocation and phosphorylation of downstream signaling molecules. Reference: J Drugs Dermatol. 2013 Oct;12(10):1156-62. https://jddonline.com/articles/dermatology/S1545961613P1156X
In vivo activity: The effect of treating psoriasis with a daily topical application of valrubicin cream was investigated in a psoriasis xenograft transplantation model. In vivo, valrubicin treatment resulted in a normalization of epidermal morphology and a reduction in epidermal thickness after 12 days. In addition, the dermal vessel pattern was reduced and the stratum granulosum was regained. Staining for a regenerative proliferation marker showed a decrease in keratinocyte proliferation, and scattered epidermal cells showed apoptosis. These results indicated that valrubicin successfully treats psoriasis in a xenograft transplantation model, suggesting that topical valrubicin may become an upcoming treatment for psoriasis. Reference: J Invest Dermatol. 2010 Feb;130(2):455-63. https://www.jidonline.org/article/S0022-202X(15)34692-3/fulltext

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 78.33 108.24
Ethanol 52.5 72.55
DMF 5.0 6.91

Preparing Stock Solutions

The following data is based on the product molecular weight 723.64 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.

Recalculate based on batch purity %
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. Laugesen IG, Hauge E, Andersen SM, Stenderup K, de Darkó E, Dam TN, Rosada C. Valrubicin activates PKCa in keratinocytes: a conceivable mode of action in treating hyper-proliferative skin diseases. J Drugs Dermatol. 2013 Oct;12(10):1156-62. PMID: 24085052. 2. Rosada C, Stenderup K, de Darkó E, Dagnaes-Hansen F, Kamp S, Dam TN. Valrubicin in a topical formulation treats psoriasis in a xenograft transplantation model. J Invest Dermatol. 2010 Feb;130(2):455-63. doi: 10.1038/jid.2009.277. Epub 2009 Sep 10. PMID: 19741712.
In vitro protocol: 1. Laugesen IG, Hauge E, Andersen SM, Stenderup K, de Darkó E, Dam TN, Rosada C. Valrubicin activates PKCa in keratinocytes: a conceivable mode of action in treating hyper-proliferative skin diseases. J Drugs Dermatol. 2013 Oct;12(10):1156-62. PMID: 24085052.
In vivo protocol: 1. Rosada C, Stenderup K, de Darkó E, Dagnaes-Hansen F, Kamp S, Dam TN. Valrubicin in a topical formulation treats psoriasis in a xenograft transplantation model. J Invest Dermatol. 2010 Feb;130(2):455-63. doi: 10.1038/jid.2009.277. Epub 2009 Sep 10. PMID: 19741712.

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1: Laugesen IG, Hauge E, Andersen SM, Stenderup K, de Darko E, Dam TN, Rosada C. Valrubicin Activates PKCa in Keratinocytes: A Conceivable Mode of Action in Treating Hyper-Proliferative Skin Diseases. J Drugs Dermatol. 2013 Oct 1;12(10):1156-62. PubMed PMID: 24085052.

2: Dinney CP, Greenberg RE, Steinberg GD. Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after bacillus Calmette-Guérin. Urol Oncol. 2012 May 9. [Epub ahead of print] PubMed PMID: 22575238.

3: Hauge E, Christiansen H, Rosada C, de Darkó E, Dam TN, Stenderup K. Topical valrubicin application reduces skin inflammation in murine models. Br J Dermatol. 2012 Aug;167(2):288-95. doi: 10.1111/j.1365-2133.2012.10964.x. Epub 2012 Jul 5. PubMed PMID: 22458650.

4: Sabnis N, Nair M, Israel M, McConathy WJ, Lacko AG. Enhanced solubility and functionality of valrubicin (AD-32) against cancer cells upon encapsulation into biocompatible nanoparticles. Int J Nanomedicine. 2012;7:975-83. doi: 10.2147/IJN.S28029. Epub 2012 Feb 22. PubMed PMID: 22393294; PubMed Central PMCID: PMC3289451.

5: Steinberg GD, Smith ND, Ryder K, Strangman NM, Slater SJ. Factors affecting valrubicin response in patients with bacillus Calmette-Guérin-refractory bladder carcinoma in situ. Postgrad Med. 2011 May;123(3):28-34. doi: 10.3810/pgm.2011.05.2281. PubMed PMID: 21566413.

6: Andersen SM, Rosada C, Dagnaes-Hansen F, Laugesen IG, de Darkó E, Dam TN, Stenderup K. Topical application of valrubicin has a beneficial effect on developing skin tumors. Carcinogenesis. 2010 Aug;31(8):1483-90. doi: 10.1093/carcin/bgq122. Epub 2010 Jun 16. PubMed PMID: 20554745.

7: Rosada C, Stenderup K, de Darkó E, Dagnaes-Hansen F, Kamp S, Dam TN. Valrubicin in a topical formulation treats psoriasis in a xenograft transplantation model. J Invest Dermatol. 2010 Feb;130(2):455-63. doi: 10.1038/jid.2009.277. Epub 2009 Sep 10. PubMed PMID: 19741712.

8: Wu S, Sun C, Pan Y. Preparative counter-current chromatography purification of valrubicin (AD-32) from crude synthetic drug using upright coil planet centrifuge with four multilayer coils connected in series. J Chromatogr A. 2005 May 27;1076(1-2):207-11. PubMed PMID: 15974091.

9: Randall S. Valrubicin: an alternative to radical cystectomy for carcinoma in situ of the bladder. Urol Nurs. 2001 Feb;21(1):30-1, 34-6. Review. PubMed PMID: 11998112.

10: Kuznetsov DD, Alsikafi NF, O'Connor RC, Steinberg GD. Intravesical valrubicin in the treatment of carcinoma in situ of the bladder. Expert Opin Pharmacother. 2001 Jun;2(6):1009-13. Review. PubMed PMID: 11585003.



Additional Information

Valrubicin (N-trifluoroacetyladriamycin-14-valerate, trade name Valstar) is a chemotherapy drug used to treat bladder cancer. Valrubicin is a semisynthetic analog of the anthracycline doxorubicin, and is administered by infusion directly into the bladder. It was originally launched as Valstar in the U.S. in 1999 for intravesical therapy of Bacille Calmette-Guérin (BCG)-refractory carcinoma in situ of the urinary bladder in patients in whom cystectomy would be associated with unacceptable morbidity or mortality; however, it was voluntarily withdrawn in 2002 due to manufacturing issues.Valstar was relaunched on September 3, 2009. (The above information was directly from http://en.wikipedia.org/wiki/Valrubicin).
 
DRUG DESCRIPTION
Valrubicin (N-trifluoroacetyladriamycin-14-valerate), a semisynthetic analog of the anthra-cycline doxorubicin, is a cytotoxic agent with the chemical name, (2S-cis)-2-[1,2,3,4, 6,11-hexahydro-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-4-[[2,3,6-trideoxy-3-[(trifluoroacetyl)amino]-α-L-lyxo-hexopyranosyl]oxyl]-2-naphthacenyl]-2-oxoethyl pentanoate. Valrubicin is an orange or orange-red powder that is highly lipophilic, soluble in methylene chloride, ethanol, methanol and acetone, and relatively insoluble in water. Its chemical formula is C34H36F3NO13. VALSTAR® (valrubicin) Sterile Solution for Intravesical Instillation is intended for intra-vesical administration in the urinary bladder. It is supplied as a nonaqueous solution that should be diluted before intravesical administration. Each vial of VALSTAR contains valrubicin at a concentration of 40 mg/mL in 50% polyoxyl castor oil/50% dehydrated alcohol, USP without preservatives or other additives. The solution is sterile and nonpyro-genic.
 
Mechanism of Action:
Valrubicin is an anthracycline that affects a variety of inter-related biological functions, most of which involve nucleic acid metabolism. It readily penetrates into cells, where it inhibits the incorporation of nucleosides into nucleic acids, causes extensive chromosomal damage, and arrests cell cycle in G2. Although valrubicin does not bind strongly to DNA, a principal mechanism of its action, mediated by valrubicin metabolites, is interference with the normal DNA breaking-resealing action of DNA topoisomerase II.