Cell lines

Immature rat pituitary gland cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

1-100 nM, 6 days

Applications

(Z)-4-Hydroxytamoxifen inhibited estradiol-stimulated PRL synthesis, which was more potent than tamoxifen.

Animal models

Immature rats

Dosage form

Oral administration, 5 μg/day

Application

In immature rats which received s.c. injections of 0-2 μg estradiol, (Z)-4-hydroxytamoxifen produced a dose-related decrease in uterine wet weight when compared with the estradiol-treated controls. (Z)-4-hydroxytamoxifen (5μg/day) showed antiuterotrophic effects.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

Estrogen receptors (ER) are members of the superfamily of ligand-modulated nuclear receptors that mediate the actions of steroid hormones, vitamin D, retinoids, and thyroid hormones. ER is activated in vivo when bound by naturally occurring estrogens such as 17α-estradiol. In addition to regulating these physiological processes, estrogen also plays a central role in stimulating breast cancer growth. (Z)-Tamoxifen is a first generation selective ER modulators that is currently approved by the FDA and is widely used to treat estrogen-dependent breast cancers. Its active metabolite, (Z)-4-Hydroxytamoxifen, is a potent estrogen receptor modulator.

In vitro: (Z)-4-hydroxytamoxifen binds to ER with 8-fold higher affinity than tamoxifen. It was found that only the Z isomer has the required antiestrogenic activity; the (E)-4-hydroxytamoxifen has only about 5% of its affinity for the ER [1].

In vivo: The antioestrogenic activities of (Z)-4-hydroxytamoxifen and tamoxifen were determined after oral administration. (Z)-4-hydroxytamoxifen was administered to groups of immature rats which also received s.c. injections of 0-2 μg oestradiol. Both compounds produced a dose-related decrease in uterine wet weight when compared with the oestradiol-treated controls. At a dose of 1 μg/day, the antiuterotrophic effects of (Z)-4-hydroxytamoxifen and tamoxifen were not significantly different but at 5μg/day, (Z)-4-hydroxytamoxifen was more active (P< 0.01). (Z)-4-hydroxytamoxifen therefore appears to retain its potent antioestrogenic activity after oral administration [2].

Clinical trial: Up to now, (Z)-4-Hydroxytamoxifen is still in the preclinical development stage.

Reference:
[1] Donna D.  Yu and Barry M. Forman. Simple and Efficient Production of (Z)-4-Hydroxytamoxifen, a Potent Estrogen Receptor Modulator. J. Org. Chem. 2003, 68, 9489-9491
[2] Jordan VC, Collins MM, Rowsby L, Prestwich G.  A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol. 1977 Nov;75(2):305-16.