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Transcript
Karen R. Hurd
Submitted in partial fulfillment of requirements
Organic Chemistry II
University of Wisconsin-Eau Claire
December 2010
Tamoxifen
Drug Synthesis
OCH2CH2NMe2
Tamoxifen
H3C
Medicinal Use
Tamoxifen , one of the most effective anticancer drugs ever, acts as an antiestrogen in breast tissue,
blocking the activity of endogenous estrogens, most notably estradiol , at the estrogen receptor. There
are a number of issues that limit tamoxifen's effectiveness related to the effects of tamoxifen in other
tissues. Tamoxifen acts as an estrogen in the uterus, which increases the risk of uterine disorders
involving growth of cells (proliferative action) in women taking the drug. In addition, tamoxifen's
antiestrogen activity in the central nervous system can lead to hot flashes, one of the common
complaints from women taking tamoxifen. Finally, breast cancer cells usually develop resistance to
tamoxifen despite the fact that the majority of antiestrogen-resistant tumors remain ER-positive.
Biological Mechanism
The mechanism of action of tamoxifen is complex. Clearly, its principal mechanism of action is mediated
by its binding to the estrogen receptor and the blocking of the proliferative actions of estrogen on
mammary epithelium. One suggested mechanism for this antiproliferative action is the induction by
2
Karen R. Hurd
Submitted in partial fulfillment of requirements
Organic Chemistry II
University of Wisconsin-Eau Claire
December 2010
tamoxifen of the synthesis of the cytokine transforming growth factor-β (TGF-β), which acts as a
negative autocrine regulatory molecule. However, it has also been shown that tamoxifen can induce
synthesis of TGF-β in estrogen receptor-negative cells, such as fetal fibroblasts. Moreover,
immunohistochemical studies have shown that tamoxifen induces the synthesis of TGF-β in the stromal
(mesenchymal) compartment of breast cancers, suggesting a paracrine as well as autocrine mechanism
of action, independent of an interaction with the estrogen receptor. Reports of some clinical efficacy of
tamoxifen in the treatment of women with estrogen receptor-negative breast carcinomas would appear
to be in accord with these mechanistic conclusions.
Summary of Overall Synthetic Plan
Starting with 2-phenyl-butyrophenone, a Grignard is applied to produce a tertiary alcohol, which is then
treated with acid to form the intermediate (I). The addition of 2-(dimethylamino)-ethyl chloride treated
with a base completes the reaction to produce cis, trans-tamoxifen.
H3C
O
H3C
1. Conc. HCl
2. Pyridine hydrochloride
O
II
HO
+
CH3
O
CH3
MgBr
2 - phenyl - butyrophenone
4 - methoxyphenyl magnesium bromide
(from 4 - bromoanisole)
(I)
H3C
O
N
HO
H3C
H3C
+
CH3
Cl
H3C
2 - (dimethylamino) ethyl chloride
(II)
NaOC2H5
N
CH3
cis, trans - tamoxifen
3
Karen R. Hurd
Submitted in partial fulfillment of requirements
Organic Chemistry II
University of Wisconsin-Eau Claire
December 2010
Description of Individual Reactions
Step 1: The ketone 2-phenyl-butyrophenone is reacted with the Grignard agent 4-methoxyphenylmagnesium bromide to form a tertiary alcohol (Figure I).
H3C
O
O
O
CH3
CH3
O
Mg Br
Mg Br
CH3
Step 2: A concentrated acid (HCl) is used to remove the CH3 from the oxygen attached to the ring. This
is done by Cl- that attacks the carbon. The electrons are pushed onto the ring, making the ring with the
oxygen and the ring’s other substituents a good leaving group. H+ ion protonates the OH group, making
a H2O group (a good leaving group.) The H2O leaves and the electrons are pushed into a carbon-carbon
double bond. The result is figure II.
H3C
O
HO
+
1. Conc. H+Cl2. Pyridine hydrochloride
HO
CH3
CH3
II
Cl CH3
4
Karen R. Hurd
Submitted in partial fulfillment of requirements
Organic Chemistry II
University of Wisconsin-Eau Claire
December 2010
Step 3: The molecule is reacted with 2-(dimethylamino)-ethyl chloride using a base (NaOC2H5) in a Sn2
reaction to produce the cis, trans-tamoxifen.
H3C
Cl
N
HO
+
H3C
H3C
O
N
NaOC2H5
H3C
Sn 2
CH3
CH3
II
5
Karen R. Hurd
Submitted in partial fulfillment of requirements
Organic Chemistry II
University of Wisconsin-Eau Claire
December 2010
Annotated Bibliography
Structure illustration of tamoxifen:
Kenichiro Itami; Kamei, Toshiyuki; and Yoshida, Jan-ichi, “Diversity-Oriented Synthesis of Tamoxifentype Tetras Substituted Olefins.” Journal of American Chemical Society, 2003, 125, 14670-14671, Dec.
22, 2003.
Medical use:
Rickert, Emily L.; Trebley, Joseph P.; Peterson, Anton C.; Morrell, Melinda M.; Weatherman, Ross V.,
“Synthesis and Characterization of Bioactive Tamoxifen-conjugated Polymers.” Department of
Medicinal Chemistry and Molecular Pharmacology and the Purdue Cancer Center, Purdue University,
575 Stadium Mall Drive, West Lafayette, Indiana 47907. National Institutes of Health Public Access.
Mechanism of Action:
Brown, William; Foote, Christopher S.; Iverson, Brent L.; Anslyn, Eric V., Organic Chemistry, 5th ed.,
Brooks/Cole Centage Learning, 2009.
Synthesis Scheme
Kleeman, Axel; Engel, Jurgen; Kutscher, Bernard, Beranard; Reichert, Dietmar, Pharmaceutical
Substances: Synthesis, Patents, Application, 4th ed., Thieme, Stuttgart, New York, 2001, pg. 1967.