‫‪Anti_estrogens‬‬

‫)‪Group no. : ( 5‬‬

‫‪Project by :‬‬

‫‪20170049‬‬ ‫حسن سامي جامع‬

‫‪20170084‬‬ ‫عبدالمنعم السيد القربة‬

‫‪20170087‬‬ ‫علي محمد ابوراضي‬

‫‪20170098‬‬ ‫عمرو محمود رشاد‬

‫‪20170116‬‬ ‫محمد شعبان شرف‬

‫‪Supervision :‬‬
‫‪Dr. Salma Elsherbeni‬‬
Anti_estrogens : also known as estrogen antagonists or
estrogen blockers , they are classes that prevent estrogen like estradiol
from mediating their biological effect in the body , they work by
blocking (ER) receptors and inhibiting or suppressing estrogen
production .

Classes :
(1) Selective estrogen receptor modulator :
A SERM is a drug that has tissue-specific cstrogenic activity. Al thought many
compounds exhibit SERM activity,a few agents are antagonists in all tissues.

# Tamoxifen

# Torenifene

# Clomiphene

# Raloxifene

# Fulvestrant

(2) Aromatase inhibitor : Aromatase is a cytochrome p-450 enzyme

complex that catelyzes the conversion of androstenedione to estrone and
testosterone to estradiol.Aromatase inhibitors include both steroidal and
nonsteroidal compounds.The first generation aromatase inhibitors were
aminoglutethimide,a nonsteroidal compound,and the steroid based testolactone

# Anastrozole
# Aminogluethimide
# Exemestane

# Testolactone

# Formestane
 (1) Selective estrogen receptor modulator :

Tamoxifen : Dosage form : （Nolvadex)

Chemical name :2-(4-(1,2-dipheny 1-1

buteny)phenoxy)N-N dimethylethanamine .

Synthesis :

Toremifene : Dosage form : (farestos)

Chemical name : 2-(4-(1z)-4-chloro(1,2-

dipheny 1-1 buteny)phenoxy)N-N
dimethylethanamine .
Clomiphene : Dosage form : (Clomiphene)

Chemical name : 2(4-2 chloro-1,2

diphenylethenyI)phenoxy)N,N diethylethan
amine .
Raloxifene : Dosage form : (Evista)

Chemical name :
(6-hydroxy-2-(4-hydroxypheny1)benzo(b)
thien -3-y1)(4-(2-(1- ：2门1 piperidiny
1)ethoxy 1)methanone .

Fulvestrant : Dosage form : (faslodex)

Chemical name : 7a(9-(4,4,5,5,5-penta

fluoropenty 1)sulfiny1)nonyl)esta-1.3.5(10)
triene-3,17-diol .
 (2) Aromatase inhibitor : ❖
Anastrozole : Dosage form : (arimidex)

Chemical name : a.a a'a'tetramethy1 5-(1/

1,2,4-triazol-l-ylmethyl) 1.3 2enediacetonitrile .

Synthesis :

Aminogluethimide : Dosage form : (orimeten)

Chemical name : 3(-4-aminophenyl) 3-

ethyl-1-2,6 pipridindione .
Synthesis :
Exemestane :
Dosage form : (Aromasin)

Chemical name : 6-methylenandrosta 1,4-

diene-3, 17-dione .

Testolactone : Dosage form : (Teslac)

Chemical name : 13-hydroxyl-3-oxo13,17

secoandrosta _ 1,4-dien-17-oic acid &lactone .
Synthesis :

Formestane :

Dosage form : (Formestane)

Chemical name : 4 hydroxy androst-4-ene

3,17 dione .
Synthesis :
(3) Recently released drugs :

(A) Bazedoxifene :
Class : 2-phenylindole of third-generation selective
estrogen receptor modulator (SERM).

Iupac name : 1-[4-[2-(azepan-1-yl)ethoxy]benzyl]-2-(4-

hydroxyphenyl)-3-methyl-1H-indol-5-ol

Chemical structure :

Mechanism of action :

Dosage form :

! Bazedoxifene is used in the treatment of postmenopausal osteoporosis and an antagonist

of estrogen receptor in different tissues .
(B) Ospemifene :
Class : Deaminohydroxytoremifene selective estrogen
receptor modulator (SERM).

Iupac name : 2-(p-((Z)-4-chloro-1,2-diphenyl-1-

butenyl)phenoxy)ethanol .

Chemical structure :

Mechanism of action :

Dosage form :

! Ospemifene is an estrogen antagonist that makes vaginal tissue thicker and less fragile
resulting in a reduction in the amount of pain women experience with sexual intercourse.
(C) Ormeloxifene :
Class : phenoxy ethyl pyrrolidine selective estrogen
receptor modulator (SERM).

Iupac name : 1-[2-[4-[(3S,4S)-7-methoxy-2,2-dimethyl-3-

phenyl-chroman-4-yl]phenoxy]ethyl]pyrrolidine .

Chemical structure :

Mechanism of action :

Dosage form :

! Ormeloxifene is primarily used as a contraceptive but may also be effective for dysfunctional
uterine bleeding and advanced breast cancer, In some parts of the body, its action estrogenic (e.g.,
bones), in other parts of the body, its action is antiestrogenic (e.g., uterus, breasts ) .
(D) Chlorotrianisene :
Class : nonsteroidal estrogen and partial selective estrogen
receptor modulator (SERM).

Iupac name : 1,1',1''-(2-chloroethene-1,1,2-triyl)tris(4-

methoxybenzene); 11-chloro-4,13-dimethoxy-12-(p-
methoxyphenyl)stilbene .

Chemical structure :

Mechanism of action :

Dosage form :

! shows some properties of a selective estrogen receptor modulator, with predominantly

estrogenic activity but also some antiestrogenic activity. CTA itself is inactive and is a
prodrug in the body.
(E) Letrozole :
Class : an aromatase inhibitor anti-estrogen .
Iupac name : 4,4'-((1H-1,2,4-triazol-1-
yl)methylene)dibenzonitrile .

Chemical structure :

Mechanism of action :

Dosage form :

! Letrozole is approved by the (FDA) for treatment of local or metastatic breast cancer that
is hormone receptor positive or has an unknown receptor status in postmenopausal women.

! It is an aromatase inhibitor anti-estrogen which is used in the treatment of hormonally-

responsive breast cancer after surgery.
(f) Fadrozole :
Class : is a selective, nonsteroidal aromatase inhibitor ANTI-
ESTROGEN .

Iupac name : 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-

5-yl)benzonitrile .

Chemical structure :

Mechanism of action :

Dosage form :
sold under the brand name Afema (by Novartis) which is or
has been used in Japan for the treatment of breast cancer.

! is a selective, nonsteroidal aromatase inhibitor ANTI-ESTROGEN has been used for

treatment of breast cancer .
 (Assay of tamoxifen)
# Preparation of tamoxifen citrate :
A 1 mg ml-~ standard solution of tamoxifen citrate prepared in a DMF: H20 (1:5) mixture by
warming was used as such .

# Method for assay :

Aliquots of drug standard solution (1.0- 5.0 ml, 1 mg ml- ~) were transferred to a
series of 125ml separatory funnels, and 2.0ml of buffer (pH 2.0) and 5.0 ml of CTC
solution were added to each. The total volume of the aqueous phase in each
separatory funnel was adjusted to 12.0 ml with distilled water. After the addition of
10ml of benzene the contents were shaken for 2min. The two phases were allowed
to separate and the absorbances of the benzene layers were measured at 635 nm
against a reagent blank. The amount of drug was computed from the Beer-Lambert
plot.

# British Pharmacopoeia reference method :

Twenty tablets were massed and powdered. To a quantity of the powder containing
the equivalent of 25 mg of tamoxifen, 100ml of methanol were added. The mixture
was shaken for 15min, and the volume was adjusted 250 ml with methanol. After
filtration, 10 ml of the filtrate were diluted to 100ml with methanol, and the
absorbance of the resulting solution was measured against a methanol blank at 275
nm. The content of the drug was computed from caluculations :

𝐴𝑢𝑛 𝐶𝑢𝑛
=
𝐴𝑠𝑡 𝐶𝑠𝑡

𝐶𝑢𝑛
%Recovery = × 100
𝐶𝑡ℎ
 (Assay of Letrozole)
# Method 1 :
For the analysis of the dosage form, twenty tablets of letrozole (2.5 mg) were ground
to fine powder and mixed thoroughly. Powder equivalent to 10 mg of drug was
transferred to a 100 ml volumetric flask and dissolved in about 40 ml methanol by
shaking on a rotary flask shaker for 2 h. The solution was filtered through Whatman
filter paper ,The filter paper was washed with the blank. The washings were added
to the filtrate and the final volume was made up to 100 ml with the blank. After
suitable dilution, the absorbance of final sample corresponding to 12 mg/ml was
recorded against the blank at 238 nm. All determinations were conducted in
triplicate. The data were analyzed by linear simple regression by the least-squares
method. The recoveries were determined by adding known amounts of letrozole
reference substance (0, 20, 40, 60 and 80 mg) to the samples at beginning of the
process. A recovery exercise was then performed. The precision and accuracy of the
assay as well as linearity of the calibration curve were determined for intra- and
inter-day on three different days. The precision was expressed as the percent
coefficient of variation of each curve. The statistical data were calculated by ANOVA

# method 2 :
UV-spectrophotometry Series dilutions of the stock solution were made by pipetting
out 0.025, 0.05, 0.1, 0.25, 0.5, 1.0, and 2.0 ml stock solution into separate 10 ml
volumetric flasks and diluting to volume with methanol to produce concentrations
ranging from 0.25 – 20.0 μgml-1. The above-mentioned solutions were scanned over
the range of 400 nm to 200 nm against the blank. The λmax was found to be at 240.0
nm. The calibration curve was constructed by plotting the concentration (0.25 – 20.0
μgml-1) versus absorbance, at 240.0 nm.
# method 3 :
Area under curve The AUC (area under curve) method is applicable where there is no
sharp peak or when broad spectra are obtained. It involves calculation of the
integrated value of absorbance with respect to the wavelength between the two
selected wavelengths λ1 and λ2. The area calculation processing item calculates the
area bound by the curve and the horizontal axis. The horizontal axis is selected by
entering the wavelength range over which the area has to be calculated. This
wavelength range is selected on the basis of repeated observations, so as to get the
linearity between the area under curve and concentration. The spectra obtained in
method 2 were used to calculate the AUC. The calibration curve was constructed by
plotting the concentration (0.25 – 20.0 μg ml-1) versus AUC.