| Identification | Back Directory | [Name]
Valrubicin | [CAS]
56124-62-0 | [Synonyms]
ad32
CS-703
Valstar
Valtaxin
Aids004409
VALRUBICIN
nsc-246131
Aids-004409
antibioticad32
Valrubicin(R&D)
Valrubicin(R&
Valrubicin (AD-32)
Valrubicin (100 mg)
Valrubicin USP/EP/BP
Vinorelbine (BICINS )
VALSTAR; VALTAXIN; AD-32
VALRUBICIN/CAS NO. 56124-62-0
trifluoroacetyl-adriamyci14-valerate
trifluoroacetyladriamycin-14-valerate
n-trifluoroacetyladriamycin14-valerate
n-trifluoroacetyldoxorubicin14-valerate
n-trifluoroacetyladriamycin-14-valerate
[2-Oxo-2-[(2S,4S)-2,5,12-trihydroxy-4-[5-hydroxy-6-methyl-4-[(2,2,2-trifluoroacetyl)amino]oxan-2-yl]oxy-7-methoxy-6,11-dioxo-3,4-dihydro-1H-tetracen-2-yl]ethyl] pentanoate
(8S,10S)-8-(Valeryloxymethylcarbonyl)-10-[(3-trifluoroacetylamino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione
Pentanoic Acid 2-[(2S,4S)-1,2,3,4,6,11-Hexahydro-2,5,12-trihydroxy-7-Methoxy-6,11-dioxo-4-[[2,3,6-trideoxy-3-[(2,2,2-trifluoroacetyl)aMino]-α-L-lyxo-hexopyranosyl]oxy]-2-naphthacenyl]-2-oxoethyl Ester
(2S-cis)-Pentanoic acid, 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)-.alpha.-L-lyxo-hexopyranosyl)oxy)-2-naphthacenyl)-2-oxoethyl ester
Pentanoic acid, 2-[(2S,4S)-1,2,3,4,6,11-hexahydro-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-4-[[2,3,6-trideoxy-3-[(2,2,2-trifluoroacetyl)amino]-a-L-lyxo-hexopyranosyl]oxy]-2-naphthacenyl]-2-oxoethyl este
r
PENTANOIC ACID,2-[(2S,4S)-1,2,3,4,6,11-HEXAHYDRO-2,5,12-TRIHYDROXY-7-METHOXY-6,11-DIOXO-4-[[2,3,6-TRIDEOXY-3-[(2,2,2-TRIFLUOROACETYL)AMINO]-A-L-LYXO-HEXOPYRANOSYL]OXY]-2-NAPHTHACENYL]-2-OXOETHYLESTER (CAS NO.56124-62-0) | [EINECS(EC#)]
680-664-1 | [Molecular Formula]
C34H36F3NO13 | [MDL Number]
MFCD01939322 | [MOL File]
56124-62-0.mol | [Molecular Weight]
723.64 |
| Chemical Properties | Back Directory | [Melting point ]
116-117 °C | [Boiling point ]
135-136 C | [density ]
1.3473 (estimate) | [storage temp. ]
Sealed in dry,2-8°C | [solubility ]
DMSO (Slightly), Methanol (Slightly) | [form ]
Solid | [pka]
7.34±0.60(Predicted) | [color ]
Red | [Water Solubility ]
insoluble | [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| |
| Hazard Information | Back Directory | [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) | [Uses]
Chemotherapy drug used to treat cancer of 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.
| [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. |
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