Description
Docetaxel, a semi-synthetic product from the taxoid family, was launched in
1995 first in South Africa and subsequently in several other markets for the treatment of
ovarian, breast and non-small cell lung cancers. Like the naturally occurring antitumor
agent paclitaxel, the first marketed taxoid, docetaxel promotes both the rate and extent
of tubulin assembly into stable microtubules and inhibits their depolymerization. It acts
as a mitotic spindle poison and induces a mitotic block in proliferating cells. This
mechanism of action for taxoids is unique from other classes of anticancer agents.
Docetaxel was reported to be twice as potent as paclitaxel in several in vitro protocols
and also exhibit higher cytotoxicity. Clinical trials are on going for docetaxel for other
types of tumors including pancreatic, gastric, head and neck cancers and soft tissue
sarcomas.
Chemical Properties
Off-white Cryst
Originator
Rhone-Poulenc Rorer (France)
Uses
antineoplastic;binds to microtubules
Uses
Docetaxel is a semisynthetic analog of taxol that inhibits microtubule disassembly (IC50 = 0.2 μM) and inhibits cell replication (IC50 = 0.13 μM). It has proven more effective than taxol in preventing the proliferation of cancer cells. Docetaxel has applications in breast cancer and hormone-refractory prostate cancer. This product is intended for research applications.
Definition
ChEBI: A tetracyclic diterpenoid that is paclitaxel with the N-benzyloxycarbonyl group replaced by N-tert-butoxycarbonyl, and the acetoxy group at position 10 replaced by a hydroxy group.
Manufacturing Process
Taxol, a material occurring in nature, and extracted from Taxus brevifolia (i.e.
the Pacific yew tree). It consists of the A, B and C variants. Taxol is not water
soluble, thereby complicating its delivery in vivo for therapeutic purposes.
A sample of Taxol (14.7 g, 17 mmol) was dissolved in pyridine (150 mL) and
chlorotriethylsilane (23.03 g, 147 mmol) was added. The reaction was stirred
at 25°C under N2. After 20 hours the reaction appeared complete by TLC
analysis (7% MeOH/CH2Cl2). The mixture was concentrated to remove the
pyridine. The residue was dissolved in CH2Cl2 and washed with water, 10%
CuSO4, NaHCO3 and brine successively. The organic layer was dried over
MgSO4, and concentrated to yield 20.89 g of the crude 2,7'-bis(triethylsilyl)
Taxol. A portion of crude 2',7-bis(triethylsilyl) Taxol (14.50 g, 13.4 mmol) was
dissolved in dry THF (150 mL). Zirconocene chloride hydride (7.75 g, 30.2
mmol) was added. The reaction was stirred at 25°C under N2. After 20 hours
the reaction appeared complete by TLC analysis. The mixture was poured intocold hexanes, and the resulting precipitated Zr complexes were filtered off.
The solution was concentrated to yield 17 g of the crude 2,7'-bis(triethylsilyl)
Taxol imine. A portion of crude 2',7-bis(triethylsilyl) Taxol imine (8.36 g) was
dissolved in 1% HCl/EtOH (180 mL) and the reaction was stirred at 25°C for
20 hours. The reaction appeared complete by TLC analysis. The mixture was
poured into 800 mL of water and washed with hexane (180 mL times 3). The
aqueous layer was neutralized with NaHCO3 to pH=7.0. The product was
extracted with CH2Cl2. The organic layer was removed and concentrated to a
solid. Silica gel chromatography (5% MeOH/CH2Cl2) yielded Taxol primary
amine (2.41 g, 52% overall yield based on 5 g of Taxol used). Melting point
160°C-162°C.
A sample of Taxol primary amine (100 mg, 0.13 mmol) was dissolved in
CH2Cl2 (10 mL) and HCl (15 mM in Et2O; 10 ml, 150 mmol) was added. The
reaction was stirred at 25°C for 2 minutes. The mixture was concentrated to
remove the solvents. The residue was redissolved in CH2Cl2 and precipitated
in hexane. Filtration yielded 85 mg of Taxol PA (PA-primary amine) HCl
(83%). Melting point 65°C. A sample of Taxol PA HCl (50 mg, 0.064 mmol)
was dissolved in 0.5 ml of water. It was neutralized to pH 7.0 by addition of
saturated NaHCO3, followed by extraction with CH2Cl2. The organic layer was
concentrated and chromatographed (3% MeOH/CH2Cl2was used as mobile
phase) to yield 30 mg of Taxol primary amine (63% yield). The 1H NMR and
LRMS data agree well with a standard sample of Taxol primary amine.
Trimethylsilyl- and trichlorethoxycarbonyl-protecting group can be used. A
mixture of impure Taxol A, B, C can be converted Taxol primary amine, which
then can be converted to Taxol A or docetaxel.
Brand name
Taxotere (Sanofi Aventis).
Therapeutic Function
Antitumor
Hazard
A poison. Human systemic effects.
Clinical Use
Antineoplastic agent:
Treatment of breast cancer, prostate cancer and
non-small cell lung cancer unresponsive to alternative
therapies, also gastric adenocarcinoma, squamous cell
carcinoma of head and neck
Metabolism
A study of [14C]-docetaxel has been conducted in
three cancer patients. Docetaxel was eliminated in
both the urine and faeces following cytochrome P450
3A4-mediated oxidative metabolism of the tert-butyl
ester group, within seven days, the urinary and faecal
excretion accounted for about 6% and 75% of the
administered radioactivity, respectively. About 80% of
the radioactivity recovered in faeces is excreted during
the first 48 hours as one major inactive metabolite and
3 minor inactive metabolites and very low amounts of
unchanged medicinal product.
storage
4°C, protect from light
References
1) Fabbri et al. (2008), Mitotic catastrophe and apoptosis induced by docetaxel in hormone-refractory prostate cancer cells; J. Cell Physiol, 217 494
2) Dosso and Berthold (2008), Docetaxel in the management of prostate cancer: current standard of care and future directions; Expert Opin. Pharmacother, 9 1969
3) Homma et al. (2008), RPN2 gene confers docetaxel resistance in breast cancer; Nat. Med., 14 939
4) Kars et al. (2008), Reversal of Multidrug Resistance by Synthetic and Natural Compounds in Drug-Resistant MCF-7 Cell Lines; Chemotherapy, 54 194
5) Wallin et al. (2012), GDC-0941, A Novel Class I Selective PI3K Inhibitor, Enhances the Efficacy of Docetaxel in Human Breast Cancer Models by Increasing Cell Death In vitro and In vivo; Clin Cancer Res.,?18 3901
6) Heinemann et al. (2011), Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer; BMC Cancer, 11 221
