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HomeProduct name listValrubicin

Valrubicin

  • CAS NO.:56124-62-0
  • Empirical Formula: C34H36F3NO13
  • Molecular Weight: 723.64
  • MDL number: MFCD01939322
  • EINECS: 680-664-1
  • SAFETY DATA SHEET (SDS)
  • Update Date: 2024-11-19 20:33:22
Valrubicin Structural

What is Valrubicin?

Toxicity

The primary anticipated complications of overdosage associated with intravesical administration would be consistent with irritable bladder symptoms. Myelosuppression is possible if valrubicin is inadvertently administered systemically or if significant systemic exposure occurs following intravesical administration (e.g., in patients with bladder/rupture perforation). The maximum tolerated dose in humans by either intraperitoneal or intravenous administration is 600 mg/m2.

Description

Valrubicin was launched as a new 'chemotherapeutic agent for the treatment of bladder cancer, particularly in patients with BCG-refractory carcinoma in situ (CIS) of the bladder for whom immediate cystectomy is unacceptable. It belongs to the class of anthracyclines, the widest used in human cancers, and is a N-trifluoroacetyl 14-valerate derivative of doxorubicin.Valrubicin can be obtained in 3 steps from daunomycin by N-trifluoroacetylation of the sugar moiety then iodination of the 2-acetyl group and introduction of a valerate residue. A proposed mechanism involved in the cytotoxicity of Valrubicin coud be the blockade of SV40 large T antigen helicase; this cellular enzyme is involved in the formation of a ternary complex with DNA to maintain the topographic structure of DNA during transcription. In patients with CIS of bladder refractory to front line and second line therapies, intravesical instillation of Valrubicin resulted in a complete response with a significant rate and allowed a delay in cystectomy. Systemic absorption was minimal and accordingly produced a lower incidence of cardiotoxicity compared with doxorubicin.

Chemical properties

Red Solid

Originator

Anthra Pharm. (US)

The Uses of Valrubicin

Chemotherapy drug used to treat cancer of the bladder.

What are the applications of Application

Valrubicin is a chemotherapy drug used to treat cancer

Indications

For the treatment of cancer of the bladder.

Background

Valrubicin (N-trifluoroacetyladriamycin-14-valerate) is a chemotherapy drug commonly marketed under the trade name VALSTAR. It is a semisynthetic analog of the doxorubicin, which is an anthracycline drug. Used in the treatment of the bladder cancer, valrubicin is administered by direct infusion into the bladder.

Definition

ChEBI: Valrubicin is an anthracycline and a trifluoroacetamide.

Manufacturing Process

N-Trifluoroacetyladriamycin-14-valerate The first way. A mixture of 1.65 g of 14-iodo-N-trifluoroacetyldaunomycin, prepared and purified according to the procedure of Arcamone et al., U.S. Pat. No. 3,803,124, and 1.37 g of sodium valerate in 165 ml of anhydrous acetone was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and filtered, and the filter cake was washed with anhydrous acetone until the washings were no longer colored. The combined filtrate and washings were evaporated to dryness under reduced pressure. The residue was treated with a 1:1 mixture of water and chloroform (total volume 200 ml), and the aqueous layer was separated and discarded. The chloroform extract was washed twice with cold water, once with aqueous pH 7 buffer, and finally with saturated aqueous sodium chloride. The chloroform solution was dried over sodium sulfate and the chloroform solvent was removed by evaporation under reduced pressure. The residue was dissolved in a small volume of chloroform and the product was precipitated by the addition of petroleum ether (b.p. 38°-49°C). Three additional precipitations from chloroform and petroleum ether afforded 1.36 g of N_x0002_trifluoroacetyladriamycin-14-valerate, m.p. 135°-136°C, in analytical purity and homogeneous by thin layer chromatography (silica gel G; chloroform:methanol:water, 120:20:1 by volume) and high pressure liquid chromatography.
The second way. A suspension of 750 mg of 14-bromodaunomycin hydrochloride, prepared as described in Arcamone et al. U.S. Pat. 3,803,124, and 2.48 g of powdered sodium valerate in 520 ml of anhydrous acetone was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with anhydrous acetone until the washings were free of color. The combined filtrate and washings were evaporated to dryness under reduced pressure. The residue was dissolved in 150 ml of 0.1 N HCl and the aqueous acid solution was extracted with three 50 ml portions of chloroform to remove aglycone by-products. The aqueous layer, after the addition of 3 ml of methanol, was extracted with four 25 ml portions of 1-butanol. The butanol extracts were combined and evaporated under reduced pressure at 35°C until no further distillate appeared. Filtration of the suspension at this point afforded, after thorough washing with ethyl acetate and drying, 347.7 mg of adriamycin-14-valerate hydrochloride, m.p. 176°-177°C. A second crop of 62.2 mg of product was obtained from further concentration of the filtrate at a somewhat higher temperature. Both crops of material were of high purity by thin layer chromatographic analysis (silica gel G plates; solvent system: chloroform:methanol:water, 100:20:1 by volume). A suspension of 300 mg of adriamycin-14-valerate hydrochloride in 20 ml of ethyl acetate was treated with 0.45 ml of trifluoroacetic anhydride in small portions over a few minutes until all solids had dissolved. The solution was mixed immediately with equal portions of water and chloroform (total volume 100 ml). The chloroform layer was separated and washed once with water and twice with pH 7 aqueous buffer. The chloroform solution was dried over sodium sulfate and then was evaporated to dryness under reduced pressure. The residue was dissolved in 25 ml of methanol, and the resulting solution was heated at reflux for 5 minutes, then cooled and evaporated to dryness. The residue was redissolved in 4 ml of chloroform, and the crude product was precipitated by the addition of 20 ml of petroleum ether (b.p. 38°-49°C). The crude material was purified by chromatography on a silicic acid column. Elution with chloroform containing 0.75% ethanol afforded 181 mg of Ntrifluoroacetyladriamycin-14-valerate, identical chromatographically and by spectral comparison with samples of product prepared as described above. The third way. A suspension of 193.4 mg of adriamycin free base in 20 ml of methylene chloride and 20 ml of dry dioxane was treated with 1.2 ml of trifluoroacetic anhydride with stirring at room temperature. The clear solution was diluted with chloroform and the organic layer was extracted with water. The chloroform solution was then washed with two 20 ml portions of aqueous pH 10 buffer, and then was dried over sodium sulfate. The dried chloroform solution was evaporated under reduced pressure. The residue was dissolved in 40 ml of methanol, and the methanol solution was heated at reflux for 5 minutes. The methanol solvent was then evaporated to dryness to give a residue which weighed 189.3 mg. Of this residue 170 mg was purified by chromatography on a column of silicic acid. Elution with chloroform containing 20% ethyl acetate by volume afforded 90.8 mg of pure Ntrifluoroacetyladriamycin.A solution containing 5.0 mg of N-trifluoroacetyladriamycin dissolved in 0.5 ml of anhydrous pyridine was treated with 18 microliters of valeryl chloride, which was added in small portions over a two-day period. The reaction was monitored by thin layer chromatography and when the presence of Ntrifluoroacetyladriamycin could no longer be observed, the reaction mixture was diluted with 10 ml of chloroform. The chloroform solution was extracted three times with pH 4 buffer and once with pH 7 buffer. The dried chloroform solution was then evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography on silica gel G with chloroform:methanol:water (120:20:1 by volume) as the solvent system. The major orange-colored band was removed and washed free of silica gel with a mixture of methanol and ethyl acetate. Upon evaporation of the methanol and ethyl acetate, 2.19 mg of N-trifluoroacetyladriamycin-14-valerate was obtained. This material was idential by spectral and chromatographic comparison with samples of N-trifluoroacetyladriamycin-14-valerate prepared by earlier described methods.

brand name

Valstar (Valera).

Therapeutic Function

Antineoplastic

General Description

Valrubicin is available in 200-mg vials for intravesicular administrationin the treatment of bladder cancer (orphan drugstatus). The increased lipophilicity associated with the valericacid ester and trifluoro acetate functionalities increasestissue penetration and remains intact because, in large measure,of the lack of exposure to hydrolyzing enzymes causedby direct delivery into the bladder followed by voiding ofthe instilled solution. This local action also minimizes cardiotoxicityand other adverse effects seen with other anthracyclines.The major adverse effects that are seen are bladderirritation and reddening of the urine.

Mechanism of action

Valrubicin is an anthracycline that affects a variety of interrelated biological functions, most of which involve nucleic acid metabolism. In cells, it inhibits the incorporation of nucleosides into nucleic acids, causes chromosomal damage, and arrests the cell cycle in G2. Although valrubicin does not bind strongly to DNA, valrubicin metabolites interfere with the normal DNA breaking-resealing action of DNA topoisomerase II.

Pharmacokinetics

Valrubicin is an anticancer agent.

Clinical Use

Valrubicin currently has orphan drug status in the treatment of bacille Calmette-Guérin (BCG)–refractory bladder cancer (the total patient population is ~1,000 individuals) and is used with patients for whom surgical intervention would result in high morbidity or death.

Side Effects

The most commonly reported adverse reactions are abdominal pain, urinary tract infection, hematuria, and dysuria. Systemic exposure to the drug and its metabolites would, of course, be greater in patients whose bladder wall integrity has been compromised by disease, and these patients should not receive valrubicin.

Safety Profile

Poison by intraperitoneal route.Human mutation data reported. When heated todecomposition it emits toxic fumes of Fí and NOx.

Metabolism

It is administered directly into the bladder through a catheter (intravesically). The lipophilic drug is water insoluble, but it dissolves in an aqueous vehicle that includes polyoxyethylene glycol and ethanol. The patient retains the drug in the bladder for 2 hours, then voids the solution in the normal fashion. Valrubicin is active as administered, and despite the fact that hydrolysis of the ester and trifluoroacetamide can be envisioned, it is excreted essentially unchanged. Less than 1% of an administered dose is absorbed systemically, so there is essentially no exposure to metabolizing enzymes. The reduced C13-alcoholic metabolite does not form to any appreciable extent during the 2-hour treatment period. Therapy is considered to be almost exclusively local, and there is little risk for cardiac toxicity, bone marrow suppression, drug–drug interactions, or other side effects.

Metabolism

Valrubicin is metabolized to two primary metabolites: N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol.

Properties of Valrubicin

Melting point: 116-117 °C
Boiling point: 135-136 C
Density  1.3473 (estimate)
storage temp.  2-8°C
solubility  DMSO (Slightly), Methanol (Slightly)
form  Solid
pka 7.34±0.60(Predicted)
color  Red
Water Solubility  insoluble

Safety information for Valrubicin

Computed Descriptors for Valrubicin

InChIKey ZOCKGBMQLCSHFP-XGMQQLFPNA-N
SMILES C12=C(O)C3=C(C(=O)C4C=CC=C(OC)C=4C3=O)C(O)=C1C[C@@](O)(C(=O)COC(=O)CCCC)C[C@@H]2O[C@@H]1O[C@H]([C@@H](O)[C@@H](NC(=O)C(F)(F)F)C1)C |&1:21,34,36,38,39,41,r|

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