| Identification | More | [Name]
Paclitaxel | [CAS]
33069-62-4 | [Synonyms]
7,11-methano-5h-cyclodeca[3,4]benz[1,2-b]oxete benzenepropanoic acid deriv.
BACCATIN III
BACCATIN III N-BENZYL-BETA-PHENYLISOSERINE ESTER
N-BENZYL-BETA-PHENYLISOSERINE ESTER
PACLITAXEL
PACLITAXEL, TAXUS BREVIFOLIA
PACLITAXEL, TAXUS SPECIES
PACLITAXOL
taxal
TAXOL
taxol a
TAXOL EQUIVALENT
TAXOL(R)
TAXOL(TM)
[2ar-[2aalpha,4beta,4abeta,6beta,9alpha(alphar*,betas*),11alpha,12alpha,12bal
-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,11-dihydroxy-4
12a-alpha,12b-alpha))-12-alpha
4,10-diacetate2-benzoate13-esterwith(2r,3s)-n-benzoyl-3-phenylisoserine
5beta,20-epoxy-1,2alpha,4,7beta,10beta,13alpha-hexahydroxytax-11-en-9-one
-9-ylester | [EINECS(EC#)]
205-285-7 | [Molecular Formula]
C25H22O3 | [MDL Number]
MFCD00869953 | [Molecular Weight]
370.44 | [MOL File]
33069-62-4.mol |
| Chemical Properties | Back Directory | [Appearance]
White Powder | [Melting point ]
213 °C (dec.)(lit.)
| [alpha ]
D20 -49° (methanol) | [Boiling point ]
774.66°C (rough estimate) | [density ]
0.200 | [refractive index ]
-49 ° (C=1, MeOH) | [Fp ]
9℃ | [storage temp. ]
2-8°C
| [solubility ]
methanol: 50 mg/mL, clear, colorless
| [form ]
powder
| [pka]
11.90±0.20(Predicted) | [color ]
white
| [Stability:]
Stable. Incompatible with strong oxidizing agents. Combustible. | [Water Solubility ]
0.3mg/L(37 ºC) | [Usage]
An antineoplastic. Used in the study of structure and function of microtubles into tubulin | [λmax]
227nm(MeOH)(lit.) | [Merck ]
6982 | [BRN ]
1420457 | [InChIKey]
RCINICONZNJXQF-MZXODVADSA-N | [LogP]
3.950 (est) | [CAS DataBase Reference]
33069-62-4(CAS DataBase Reference) | [EPA Substance Registry System]
33069-62-4(EPA Substance) |
| Safety Data | Back Directory | [Hazard Codes ]
Xn | [Risk Statements ]
R37/38:Irritating to respiratory system and skin .
R41:Risk of serious damage to eyes.
R42/43:May cause sensitization by inhalation and skin contact .
R62:Possible risk of impaired fertility.
R68:Possible risk of irreversible effects.
R40:Limited evidence of a carcinogenic effect.
R48:Danger of serious damage to health by prolonged exposure.
R20/21/22:Harmful by inhalation, in contact with skin and if swallowed . | [Safety Statements ]
S22:Do not breathe dust .
S26:In case of contact with eyes, rinse immediately with plenty of water and seek medical advice .
S36/37/39:Wear suitable protective clothing, gloves and eye/face protection .
S45:In case of accident or if you feel unwell, seek medical advice immediately (show label where possible) . | [RIDADR ]
1544 | [WGK Germany ]
3
| [RTECS ]
DA8340700
| [F ]
10-21 | [HazardClass ]
6.1(b) | [PackingGroup ]
III | [HS Code ]
29329900 | [Hazardous Substances Data]
33069-62-4(Hazardous Substances Data) | [Toxicity]
LD50 intraperitoneal in mouse: 128mg/kg |
| Raw materials And Preparation Products | Back Directory | [Raw materials]
Ethyl acetate-->Silica gel-->Celite-->Triethylamine trihydrofluoride-->Benzoyl chloride-->hydrogen fluoride-->tert-Butylisocyanate-->Sodium bicarbonate-->4-Nitrobenzenesulfonyl chloride-->Benzaldehyde dimethyl acetal-->Triethylamine-->Chlorotrimethylsilane-->Thiophenol-->p-Toluenesulfonic acid-->Potassium tert-butoxide-->Hydrogen fluoride | [Preparation Products]
(αR,βS)-β-(BenzoylaMino)-α-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-benzenepropanoic Acid (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-Bis(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodeca |
| Hazard Information | Back Directory | [General Description]
Needles (from aqueous methanol) or fine white powder. An anti-cancer drug. | [Air & Water Reactions]
May be sensitive to prolonged exposure to moisture. . | [Health Hazard]
TOXIC; inhalation, ingestion or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. | [Fire Hazard]
Flash point data for this chemical are not available. TAXOL is probably combustible. | [Description]
Paclitaxel(33069-62-4), a natural product isolated from the bark of the Pacific yew, is effective in
treating refractory metastatic ovarian cancer. Unlike any other antineoplastic agents,
paclitaxel appears to have several possible mechanisms of action, including an
antimicrotubule action through the promotion of tubulin polymerization and stabilization of
microtubules, thereby, halting mitosis and promoting cell death. The supply of paclitaxel is
limited by its low natural abundance and currently it is being manufactured by a semi-synthetic
route from deacetylbaccatin Ⅲ that is isolated from the needles of the yew tree. Recent
completion of two total syntheses of taxol conquered the structural complexity of the title
compound and may be useful in obtaining certain closely related analogs, some of which have
been found to have antitumor activity. Paclitaxel has potential uses in the treatment of
metastatic breast cancer, lung cancer, head and neck cancer, and malignant melanoma.
| [Chemical Properties]
White Powder | [Physical properties]
Appearance: Odorless and tasteless white or kind of white crystal powder. Solubility: Poorly soluble in water but slightly soluble in ether. Soluble in methanol, acetonitrile, chloroform, acetone, and other organic solvents. Melting point: 213–216?°C. Specific optical rotation: ?49° (C?=?1, MeOH); Curl: 20° to D?=?49.0–55.0° (10?mg/mL of methanol solution) in anhydrous dry goods without solvents. | [Originator]
NIH (U.S.A.) | [History]
The toxic ingredients in branches and leaves of Taxus chinensis were separated in 1856 and named “taxine,” which was identified as a kind of white alkaloid’s component. Currently, among all the antitumor drugs, the sale of paclitaxel becomes the
first in the world as a well-recognized anticancer drug with potent broad-spectrum
activity. In October of 1995, China became the second country with formal production of paclitaxel and its injection in the world. The achievement was gained under
the unremitting efforts of researchers in the Institute of Materia Medica, Chinese
Academy of Medical Sciences. | [Uses]
An antineoplastic. Used in the study of structure and function of microtubles into tubulin. Paclitaxel is now used to treat patients with lung, ovarian, breast cancer, head and neck cancer, and advanc
ed forms of Kaposi's sarcoma. Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. | [Uses]
glucocorticoid, antiinflammatory | [Uses]
Tool in study of structure and function of microtubules. | [Definition]
ChEBI: Paclitaxel is a tetracyclic diterpenoid isolated originally from the bark of the Pacific yew tree, Taxus brevifolia. It is a mitotic inhibitor used in cancer chemotherapy. Note that the use of the former generic name 'taxol' is now limited, as Taxol is a registered trade mark. It has a role as a microtubule-stabilising agent, a metabolite, a human metabolite and an antineoplastic agent. It is a tetracyclic diterpenoid and a taxane diterpenoid. It is functionally related to a baccatin III. | [Indications]
Paclitaxel (Taxol) is a highly complex, organic compound
isolated from the bark of the Pacific yew tree. It
binds to tubulin dimers and microtubulin filaments, promoting
the assembly of filaments and preventing their
depolymerization. This increase in the stability of microfilaments
results in disruption of mitosis and cytotoxicity
and disrupts other normal microtubular functions,
such as axonal transport in nerve fibers.
The major mechanism of resistance that has been
identified for paclitaxel is transport out of tumor cells,
which leads to decreased intracellular drug accumulation.
This form of resistance is mediated by the multidrug
transporter P-glycoprotein. | [Preparation]
The total synthesis of paclitaxel (Taxol) is described. Double Rubottom oxidation of the bis(silyl enol ether) derived from a tricarbocyclic diketone effectively installed a bridgehead olefin and C-5/C-13 hydroxy groups in a one-step operation. The novel Ag-promoted oxetane formation smoothly constructed the tetracyclic framework of paclitaxel.
Total Synthesis of Paclitaxel
The biosynthesis of paclitaxel involves the condensation of the three isoprenyl diphosphate (IPP) units with dimethylallyl diphosphate (DMAPP). Plants are unique in producing IPP and DMAPP by both the mevalonic pathway (MVA) in the cytosol or via the methylerythritol phosphate (MEP) pathway in the plastids.
Paclitaxel: biosynthesis, production and future prospects | [Manufacturing Process]
(2R,3S)-β-Phenyl-isoserine methyl ester (4.35 g, 22 mM) is dissolved in dry THF (100 ml) and the flask cooled to 0°C. To the mixture is added t-butyl isocyanate (2.8 ml, 25 mM). TLC after 15 min shows some starting material left so additional isocyanate (0.5 ml) is added. TLC after 1 h shows no starting material so the solvent is concentrated under reduced pressure to give the N(t-butylaminocarbonyl)-β-phenyl isoserine methyl ester.
Triethylamine (4.8 ml, 34.4 mmol) is added to a stirred solution of methyl (2R,3S)-phenylisoserinate (7.26 g, 31.3 mmol) in methylene chloride (80 ml) at 0°C. To this slurry of is added trimethylsilyl chloride (4.4 ml, 34.7 mmol). Additional methylene chloride (45 ml) is added. The mixture is cooled to 65°C and triethylamine (9.8 ml, 70.3 mmol) is added. p-Nitrophenylsulfonyl chloride (6.93 g, 31.3 mmol) is added. The reaction rate is too slow at -65°C so the temperature is gradually raised to 0°C. Hydrogen fluoride (10% aqueous, 5 equivalents) is added. The aqueous phase is separated from the organic (methylene chloride) phase and methanol is added to the organic phase. The methylene chloride is removed under reduced pressure and the methyl (2R,3S)-3-(4-nitrobenzenesulfonamido)-3-phenyl-2-hydroxypropionate is obtained, melting point 187-189°C.
Benzaldehyde dimethylacetal (200 μl, 1.33 mmol) and a catalytic amount of p-toluenesulfonic acid (37 mg) are added to methyl (2R,3S)-3-(4nitrobenzenesulfonamido)-3-phenyl-2-hydroxypropionate (315 mg, 0.83 mmol) in toluene 5 ml. The mixture is heated at 100°C under reduced pressure (15 mm mercury) with no condenser. After 1 h the crude reaction mixture is diluted with ethyl acetate and washed with water (2 times). After drying the organic layer over magnesium sulfate the crude material is purified by column chormatography (silica gel; eluting with ethyl acetate/cyclohexane, 35/65) to give the (2S,4S,5R)-2,4-diphenyl-3-(4-nitrobenzenesulfonamido)-5methoxycarbonyl-1,3-oxazolidine, melting point 118°-120°C.
Water (8 ml), methanol (8 ml) and THF (8 ml) are added to (2S,4S,5R)-2,4diphenyl-3-(4-nitrobenzenesulfonamido)-5-methoxycarbonyl-1,3-oxazolidine (1.50 g, 3.19 mmol). Potassium carbonate (1.018 g, 7.71 mmol) is then added. The resulting mixture is stirred at 20°-25°C until complete by TLC. After 5 h the reaction is complete and the reaction mixture is extracted with basic methylene chloride (2 times). The aqueous phase is then acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is then washed with water, saline and dried over magnesiuim sulfate. Concentration of the organic phase (ethyl acetate) gives the (2S,4S,5R)-2,4diphenyl-3-(4-nitrobenzenesulfonamido)-5-carboxy-1,3-oxazolidine, melting point 61°-65°C.
Then the (2S,4S,5R)-2,4-diphenyl-3-(4-nitrobenzenesulfonamido)-5-carboxy1,3-oxazolidine react with the 7-SDMS Baccatin III, that is 7-(3-methylbut-2yl)dimethylsilyl baccatin III (Baccatin III: 7,11-methano-1H-cyclodeca(3,4) benz(1,2-b)oxet-5-one,6,12b-bis(acetyloxy)-12(benzoyloxy)-1,2a,3,4,4a,6, 9,10,11,12,12a,12b-dodecahydro-4,9,11-trihydroxy-4a,8,13,13-tetramethyl-, (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS), isolated from Taxus baccata).
(2S,4S,5R)-2,4-Diphenyl-3-(4-nitrobenzenesulfonamido)-5-carboxy-1,3oxazolidine(323 mg, 0.711 mmol) is mixed with toluene (2.5 ml) at 20°-25°C. Dicyclohexylcarbodiimide (160 mg, 0.775 mmol) is then added to the reaction mixture. 7-SDMS Baccatin III (156 mg, 0.218 mmol) is added followed by 4(dimethylamino)pyridine (35 mg, 0.286 mmol) and the reaction mixture is stirred at 20°-25°C until complete (1 h) by TLC. Sodium bicarbonate (50% aqueous, 10 ml) and more toluene (5 ml) is added to the reaction mixture and then stirred at 20°-25°C for 2 h. The reaction mixture is filtered through a medium frit to remove the urea byproduct. After filtering the phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with aqueous sodium bicarbonate (50%), water and saline. The organic phases are dried over magnesium sulfate, filtered and then concentrated. The concentrate is purified by column chromatograpy (silica gel; eluting with ethyl acetate/cyclohexane, 20/80) to give the 7-SDMS baccatin III 13-(2R,4S,5R)- and (2S,4S,5R)-2,4-diphenyl-3(4-nitrobenzenesulfonamido)-1,3-oxazolidine-5-carboxylic acid ester.
THF (13.5 ml) and DMF (1.5 ml) are cooled to -35°C and degased by alternating reduced pressure and nitrogen three times. Thiophenol (0.22 ml, 2.14 mmol) is added followed by potassium butoxide/THF (1.978 M, 0.7 ml, 1.38 mmol). After 5 min, 7-SDMS baccatin III 13-(2R,4S,5R)- and (2S,4S,5R)-2,4-diphenyl-3-(4-nitrobenzenesulfonamido)-1,3-oxazolidine-5carboxylic acid ester (877 mg, 0.762 mmol) is added. After the solids are added, the reaction mixture is slowly warmed to -10°C. The mixture is stirred at -10°C until the red color fades to yellow. After 3 h the bath is dropped allowing the mixture to warm to 20-25°C. At 20°-25°C the reaction is stirred for 1 h before assaying by TLC and HPLC. Sodium bisulfite (241 mg, 2.31 mmol) is added in water (5 ml). The mixture is stirred at 20°-25°C and after approximately 115 h the reaction is complete (by TLC) giving the free amine 7-SDMS Sodium bicarbonate (485 mg, 5.77 mmol) and water (10 ml) are added to 7SDMS baccatin III 13-(2R,3S)-3-amino-3-phenyl-2-hydroxypropionate. The mixture is cooled to 0°C and then benzoyl chloride (150 ml, 1.3 mmol) is added. After 1 hr the reaction is complete and the reaction mixture is diluted
with water and extracted with ethyl acetate. The organic phases are combined and washed with water, saline and dried over magnesium sulfate. Chromatography of the crude product (silica gel column; 20% to 100% ethyl acetate gives the 7-SDMS baccatin III 13-(2R,3S)-3-benzamido-3-phenyl-2hydroxypropionate.
7-SDMS Baccatin III 13-(2R,3S)-3-benzamido-3-phenyl-2-hydroxypropionate (126 mg, 0.128 mmol) is dissolved in acetonitrile (2.5 ml). Triethylamine trihydrofluoride (123 mg, 0.763 mmol) is added under nitrogen and the resulting mixture is stirred at 5°C until complete by HPLC. When complete, the mixture is extracted with methyl t-butylether and washed with sodium bicarbonate solution. The aquesous washes are back extracted and combined with the organic phase. The combined organic phases are washed with water and saline, dried over magnesium sulfate, filtered and concentrated to give the Taxol (Paclitaxel), as needle from methanol with melting point 213-216°C.
baccatin
III 13-(2R,3S)-3-amino-3-phenyl-2-hydroxypropionate | [Brand name]
Abraxane (Abraxis); Taxol (Bristol-Myers Squibb). | [Therapeutic Function]
Antineoplastic | [Biological Activity]
Antitumor agent; promotes and stabilizes tubulin polymerization, causing cell cycle arrest. Induces autocatalytic activation of caspase-10 in CCRF-HSB-2 cells, triggering apoptosis. | [Biochem/physiol Actions]
Product does not compete with ATP. | [Mechanism of action]
Paclitaxel’s large volume of distribution indicates significant
tissue binding. The drug is extensively metabolized
by the liver, and doses must be reduced in patients
with abnormal liver function or with extensive liver
metastases.Very little of the drug is excreted in the urine. | [Pharmacology]
Paclitaxel is mainly used for the treatment of ovarian cancer and breast cancer. The mechanism of it includes:
1. The effects on cell microtubules/tubulin: Inhibition of microtubule depolymerization results in abnormal micro tube bundle arrangement and makes the spindle lose normal function and then induces cell death.
2. In the absence of bird triphosphate (GTP) and microtubule associated protein (MAP), it induces cells to form microtubule lack of function.
3. It significantly sensitized cancer cells to radiotherapy through blocking the cell cycle in the stage of G2 and M .
Paclitaxel is mainly metabolized through the liver and enters into the intestine with bile and then eliminated from the body by the feces (90%). | [Anticancer Research]
It is isolated from the bark of Taxus brevifolia generally known as pacific yew. It isprimarily used in ovarian, small, and non-small cell lung cancers and advancedbreast cancer (Shoeb 2006). It binds to tubulin but neither depolymerizes it nor interferes with its assembly (Balunas and Kinghorn 2005). Taxol targets activatorprotein 1 signaling pathways (Singh et al. 2016b). | [Anticancer Research]
Paclitaxel (commercial name, Taxol) a complex diterpene alkaloid isnaturally obtained from Taxus species (family Taxaceae). Paclitaxel has been provedas highly effective in the treatment of various types of cancers, since it acts as amicrotubule-stabilizing agent to protect against disassembly. Paclitaxel was developed by the National Cancer Institute, USA, as a drug for cancer therapy andused for the treatment of refractory ovarian cancer, metastatic breast and lung cancer,and Kaposi’s sarcoma (Srivastava et al. 2005). The natural source of paclitaxelis the bark of several Taxus species; however, the cost of extraction is very highsince the concentration of paclitaxel accumulation is very low (0.02% of dry weight)and also entails the destruction of natural resources (Cusido et al. 2014). Eventhough, paclitaxel can be chemically synthesized, but this process is not commerciallyviable. Plant cell cultures have been developed for the production of paclitaxelby Phyton Biotech in 1995, and in 2004 the FDA has approved the use of plantculture supply of paclitaxel/Taxol (Leone and Roberts 2013). | [Clinical Use]
Paclitaxel is among the most active of all anticancer
drugs, with significant efficacy against carcinomas of the
breast, ovary, lung, head, and neck. It is combined with
cisplatin in the therapy of ovarian and lung carcinomas
and with doxorubicin in treating breast cancer. | [Side effects]
Myelosuppression is the major side effect of paclitaxel.
Alopecia is common, as is reversible dose-related
peripheral neuropathy. Most patients have mild numbness
and tingling of the fingers and toes beginning a few
days after treatment. Mild muscle and joint aching also
may begin 2 or 3 days after initiation of therapy. Nausea
is usually mild or absent. Severe hypersensitivity reactions
may occur. Cardiovascular side effects, consisting
of mild hypotension and bradycardia, have been noted
in up to 25% of patients. | [Toxicology]
The major toxicity seen with paclitaxel is a dose-limitingmyelosuppression that normally presents as neutropenia. Thepreviously mentioned hypersensitivity reactions occur but aregreatly reduced by antihistamine pretreatment. Interactionwith the axonal microtubules such as that seen for the vincasalso occurs and leads to numbness and paresthesias (abnormaltouch sensations including burning and prickling). Theagent is also available as an albumin-bound formulation(Abraxane) to eliminate the need for the solubilizing agentsassociated with the hypersensitivity reactions. Other adverseeffects include bradycardia, which may progress to heartblock, alopecia, mucositis, and/or diarrhea. Paclitaxel producesmoderate nausea and vomiting that is short-lived. | [Drug interactions]
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine (increased risk
of agranulocytosis).
Cytotoxics: increased risk of neutropenia with
lapatinib. | [Metabolism]
The major use-limiting adverse effect of paclitaxel is dose-dependent myelosuppression, particularly neutropenia, and first doses may need to be decreased in patients with hepatic dysfunction. Subsequent dose reductions, if any, should be tailored to individual response. The drug should not be given to patients who have baseline neutrophil counts below 1,500 cells/mm3. The albumin-bound formulation also is associated with sensory neuropathy. | [storage]
4°C, protect from light | [Precautions]
1. Hermatological toxicity: the main factor in increased dosage limitations; when white blood cells are below 1500/mm3, supplement with G-CSF; when platelets are below 30000/mm3, transfuse component blood.
2. Allergic reaction: Aside from preconditions, if there are only minor symptoms such as flushed face, skin reactions, slightly increase heart rate, slightly lowered blood pressure, etc., do not stop treatment and decrease injection speed. If there are serious reactions such as hypotension, vascular edema, difficulty breathing, measles, etc., stop treatment and treat accordingly. Patients with serious allergic reactions should not use paclitaxel in the future.
3. Nervous system: Common reactions include numb toes. Approximately 4% patients, especially with high dosage, experience significant sensory and motor difficulty and decreased tendon reflex. There have been individual reports of epilepsy.
4. Cardiovascular: Transient tachycardia and hypotension are common and do not usually require attention. However, monitor closely during first hour of injection. Afterwards, only patients with serious injection difficulty require hourly check-ins.
5. Join and muscle: Approximately half of the patients will experience some joint and muscle pain within the first 2-3 days following injection, which is related to dosage, and usually subsides after a couple days. Patients who are also administered G-CSF will experience heightened muscle pain.
6. Liver and gall: As paclitaxel is mainly excreted through bile, patients with liver and gall diseases must be monitored carefully. Among thousands of cases, 8% of patients experienced increased bilirubin, 23% experienced increased alkaline phosphatase, and 18% experienced increased glutamic-oxalacetic transaminase. However, there is currently no evidence indicating that paclitaxel causes any severe liver damage.
7. Other: Digestive tract reactions are common but rarely severe, with few cases of diarrhea and mucosa infection. Slight alopecia is also common. | [References]
Wani et al.,J. Amer. Chem. Soc., 93,2325 (1971) |
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