Chemical Properties
Crystalline Solid. soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide. The solubility of anastrozole in these solvents is approximately 20, 13, and 14 mg/ml.
Originator
Zeneca (United Kingdom)
Application
Anastrozole (aromatase inhibitor) has been used:
as a positive control in DNA fragmentation (ladder) assay
to investigate its effects along with extra virgin olive oil and its major fatty acid component (omega-9 OA) in estrogen receptor positive mammary adenocarcinoma cells
to study its effects on viability, cell proliferation and apoptosis in Glioblastoma multiforme model in vivo
Definition
ChEBI: Anastrozole(120511-73-1) is a 1,2,4-triazole compound having a 3,5-bis(2-cyano-2-propyl)benzyl group at the 1-position. It has a role as an antineoplastic agent and an EC 1.14.14.14 (aromatase) inhibitor. It is a member of triazoles and a nitrile.
Preparation
synthesis of anastrozole can be realized in four steps based on 3,5-bis(bromomethyl)toluene. Starting with a S N 2 displacement using potassium nitrile and tetrabutylammonium bromide as a phase transfer catalyst to give bis-nitrile compound. Bis-nitrile compound formed undergoes deprotonation with NaH and methylated afterwards with methyl iodide to give bis-dimethyated product.Product undergoes radical substitution reaction following the Wohl-Ziegler reaction using N-bromosuccinamide and benzoyl peroxide as the radical initiator.In the final step, benzylbromide undergoes SN2 displacement with sodium triazole to give anastrozole.
Manufacturing Process
A mixture of 2,2-(5-methyl-1,3-phenylene)di(2-methylpropionitrile) (2.26 g),
N-bromosuccinimide (1.78 g), benzoylperoxide (0.05 g) and carbon
tetrachloride (50 ml) was refluxed for 2 hours, cooled and filtered, and the
filtrate was evaporated to dryness under reduced pressure. The residue was
dissolved in dimethylformamide (20 ml), sodium triazole (1.8 g) was added,
and the mixture was stirred at room temperature for 18 h. Water (100 ml)
was added, and the mixture was extracted twice with ethyl acetate, dried and
evaporated to dryness and the residue was purified by flash column
chromatography, eluting with ethyl acetate to give 2,2-[5-(1H-1,2,4-triazol-1-
ylmethyl)-1,3-phenylene]di(2-methylpropionitrile), mp 81-82°C after
crystallization from ethyl acetate/cyclohexane.
The 5-methyl-1,3-phenylene compound used as starting material in above
process may be prepared as follows. The mixture of 3,5-
bis(bromomethyl)toluene (30 g), tetrabutyl-ammonium bromide (1 g), KCN
(17.6 g), dichloromethane (100 ml) and water (30 ml) was stirred vigorously
and refluxed for 3 h. The mixture was cooled, diluted with water (100 ml) and
extracted three times with ethyl acetate, dried and evaporated to dryness, the
residue was purified by flash chromatography, eluting with petroleum
ether/ethyl acetate (3:1) to give 2,2-(5-methyl-1,3-phenylene)diacetonitrile,
mp 73-74°C after crystallization from carbon tetrachloride. A mixture of this
diacetonitrile (11.5 g), iodomethane (42 g) and dimethylformamide (150 ml)
was cooled in an ice and stirred while sodium hydride (50% dispersion in
mineral oil, 15 g) was added slowly, over 1 hour, then the mixture was
allowed to warm to room temperature, stirred for 2 h, 500 ml of water was
added, and the mixture was extracted twice with ethyl acetate, the extracts
were dried and evaporated to dryness and the residue was crystallized from
carbon tetrachloride to give the required 5-methyl-1,3-phenylene starting material, mp 126-127°C.
Brand name
Arimidex
(AstraZeneca).
Therapeutic Function
Antitumor
General Description
Anastrozole,α,α,α',α'-tetramethyl5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-benzenediacetonitrile,was the first specific aromatase inhibitor approved in theUnited States. It is indicated for first-line treatment of postmenopausalwomen with advanced or metastatic breast cancer,for second-line treatment of postmenopausal patientswith advanced breast cancer who have had disease progressionfollowing tamoxifen therapy, and for adjuvant treatmentof women with early breast cancer. Patients who did not respondto tamoxifen therapy rarely respond to anastrozole.
Biological Activity
Potent and highly selective aromatase (CYP19) inhibitor (IC 50 = 15nM) that has no discernible effect on adrenocorticoid hormone synthesis. Reduces plasma estrogen levels and exhibits antitumor activity in vivo . Orally active.
Biochem/physiol Actions
Anastrozole, which contains a triazole functional group, reversibly binds to the cytochrome P-450 component of aromatase. Binding interferes with the catalytic properties of aromatase, which results in inhibition of estrogen synthesis.
Mechanism of action
Anastrozole, a benzyltriazole derivative, competes with the natural s ubstrate for binding to the active site of the aromatase. The mechanism of enzyme inhibition resides in the coordination of the triazole ring with the hemeiron atom of the aromatase enzyme complex. This coordination ultimately prevents arom atization of androgens into estrogens and, therefore, deprives the tumor of estrogen. This effect is reversible. In the presence of anastrozole, estradiol levels are reduced to undetectable levels, with no adverse effects on levels of any other horm one, including cortisol and aldosterone.
Clinical Use
Anastrozole is a potent and highly selective, nonsteroidal aromatase inhibitor utilized in the treatment of advanced breast cancer that is horm one-responsive. It is considered to be second-line therapy (after tamoxifen) in the treatment of postm enopaus al breast cancer.
Side effects
The most common anastrozole side effects are related to lower estrogen levels in the body. They include hot flashes, nausea and vomiting, and mood changes. Anastrozole could cause your bones to thin, which raises your risk of osteoporosis. It can also cause high cholesterol.
Drug interactions
Potentially hazardous interactions with other drugs
Oestrogen-containing therapies: avoid concomitant
administration as would negate pharmacological
action.
Tamoxifen: avoid concomitant administration.
Environmental Fate
Anastrozole is classified as readily biodegradable and is moderately mobile in soils. The measured octanol-water partition coefficient is low, therefore anastrozole is not predicted to bioaccumulate in aquatic organisms.
Metabolism
Anastrozole is extensively metabolised by postmenopausal
women with less than 10% of the dose excreted in the
urine unchanged within 72 hours of dosing. Metabolism
of anastrozole occurs by N-dealkylation, hydroxylation
and glucuronidation via CYP 3A4 and 3A5, and
UGT1A4. The metabolites are excreted primarily via the
urine. Triazole, the major metabolite in plasma, does not
inhibit aromatase.
References
[1] DUKESM. The preclinical pharmacology of “Arimidex” (anastrozole; ZD1033)–a potent, selective aromatase inhibitor.[J]. Journal of Steroid Biochemistry and Molecular Biology, 1996. DOI:
10.1016/0960-0760(96)00064-7.
[2] U B. Anastrozole: a new addition to the armamentarium against advanced breast cancer.[J]. American Journal of Clinical Oncology-Cancer Clinical Trials, 1998. DOI:
10.1097/00000421-199804000-00014.
[3] L?NNINGP E DowsettM GeislerJ. Pharmacological and clinical profile of anastrozole.[J]. Breast Cancer Research and Treatment, 1998. DOI:
10.1023/a:1006000806630.
[4] HOZUMIYASUO. Effects of anastrozole on lipid metabolism compared with tamoxifen in rats.[J]. Breast Cancer Research and Treatment, 2002. DOI:
10.1023/a:1020571617274.
