50-27-1 Usage
Uses
Used in Pharmaceutical Industry:
Estriol is used as an estrogen drug for treating various conditions, including leukopenia, menopause, and menopausal syndrome. It is particularly effective in treating skin atrophy and signs of genital degeneration.
Used in Diagnostics:
Estriol serves as a primary estrogen in urine and a direct marker of fetal adrenal gland activity. It is used for monitoring estriol levels in saliva, which contains primarily unbound and unconjugated estriol.
Used in Research:
As a metabolite of estradiol, estriol is used in research to study its estrogenic effects, which are considerably less potent than the hormone estradiol. This makes it a valuable tool for understanding the role of estrogens in various biological processes.
Used in Hormone Replacement Therapy (HRT):
Estriol is used in HRT, where it can be compounded into several different formulations. It can be used alone or in combination with estradiol (Bi-Est) or with estradiol and estrone (Tri-Est) to help alleviate the mental symptoms of menopausal syndrome and support overall health during the premenopausal and menopausal periods.
Precautions:
Patients with breast hyperplasia, breast lumps, and cancer potentially related to female hormones, aplastic anemia, and liver disease should avoid using estriol. Temporary breast swelling and lumps, as well as menstrual cycle disorders, may occur but typically resolve within about one month after stopping the drug.
Natural hormone
Estriol belongs to natural hormone and is the metabolite of estradiol in vivo. It is mainly presented in the urine. Estrogen has a relative small activity with the oral activity being 6 times as high as estrone but being weaker than estradiol with non-carcinogenic effects. After its administration, the in vivo estradiol levels did not change. Estriol has selective action on the vaginal and cervical canal but has no effect on the uterus and endometrium entity. Animal experiments have shown that estriol has a stronger effect on vaginal epithelial keratosis than estradiol, thus being able to promote vaginal epithelial hyperplasia, superficial cells keratosis, mucosal angiogenesis and vaginal epithelial wound healing, but having a weak effect on the weight gain of mouse uterus. At the same time, estriol can enhance the function of cervix cell, causing the cervix muscle fiber hyperplasia and increasing the cervical elasticity and softness. In addition, estriol has feedback inhibition on the hypothalamus and pituitary but does not inhibit ovulation while only having significant impact on the corpus luteum and therefore can be used as the auxiliary drug in the medium-term labor induction and artificial abortion and for the treatment of various kinds of menopathy. Estriol also has significant effect on the hematopoietic system and can reduce vascular permeability and fragility. Therefore, it can be used for the treatment of various kinds of hemorrhage. It also has effect of rapidly increasing the peripheral leukocytes and generally begins to take effect at 1 to 3 days after treatment but with a shorter duration of action and is effective in treatment the leukopenia induced by radiotherapy and chemotherapy.
Figure 1 is the formula of estriol
Pharmacokinetics
It can be absorbed from the gastrointestinal tract and skin but is susceptible to damage upon oral administration and is therefore mainly subject to intramuscular injection and topical usage. It is metabolized in the body to less-active estrone and estriol and can be inactivated when being combined with glucuronic acid and sulfuric acid and further excreted in urine.
Indications
It can be used for treating cervicitis, especially suitable for treating menopausal syndrome and senile vaginitis. It can also be used as the adjuvant drug for middle-term labor induction and artificial abortion. It can also be used for treating prostatic hypertrophy and prostate cancer. In addition, it still has a rapid role in increasing the peripheral leukocytes. It generally takes effect at 1 to 3 days after the treatment but with a short duration period. It also has efficacy in treating leukopenia caused by chemotherapy or radiotherapy as well as reducing the vascular permeability and fragility and can be used for the treatment of various kinds of hemorrhage. It also has quick hemostasis effect on menorrhagia, hysterectomy or tonsillectomy.
Side effects
There are temporary breast swelling or lumps, menstrual disorders which can self-limiting and recovery after discontinuing the drug. In oral administration, it has been occasionally observed of loss of appetite, nausea, vomiting, abdominal pain and so on.
Determination of estriol content
Estriol is produced through the hydroxylation of carbon 16 in dehydroepiandrosterone at fetal adrenal; it further enters into the placenta and the metabolism by the placental syncytiotrophoblast cells. It is then released into the maternal blood with the free estriol absorbed by the maternal liver and further combined into glucuronic acid or sulfuric acid estriol that are further excreted by the kidneys. Therefore, the estriol in the urine is all in the form of conjugated estriol while the estriol in the blood contains both free type and bound type with free form accounting for about 10 to 30% and the rest being in bound form. Determination of estriol in the urine of pregnant women with a spectrophotometer has been widely used clinically. There are other common methods including radioimmunoassay. Estriol is not contained in the blood of non-pregnant women. According to the measurement of the Shanghai Second Medical Ruijin Hospital, upon 26 weeks of pregnancy, the plasma free estriol is 4~6ng/ml while upon 36 weeks, it is 10~12ng/ml and it is 19ng/ml or more in full term but with large individual differences. The total plasma estriol value, at 25 weeks of gestation, is 50ng/ml and is 200ng/ml at 40 weeks of pregnancy.
At 24h, the urine estriol was 8.12 ± 0.28mg at 28 weeks of pregnancy and was 19.81 ± 8.28 mg in full term. It is generally believed that after 36 weeks of pregnancy, if the urine content at 24 h > 15mg, the value is normal; 12~10mg is alert value while <10mg is dangerous values. Since the major precursor of estriol during pregnancy comes from fetus, being different from the estrone and estradiol that is from the mother, the determination of estriol may reflect the condition of fetal development. When some fetal malformations and maternal or fetal diseases affect fetal development or cause fetal asphyxia, it is always accompanied of decrease of estriol. However, due to the great daily fluctuations of estriol level, it is generally measured for 4 to 5 times at least for some time in order to determine whether the level of estriol is really low. The estriol level in mild hypertension of pregnancy are often normal before 34 weeks while is maintained at low level after 34 weeks while the level significantly drops upon severe pregnancy-induced hypertension. For pregnant women upon exceeding the expected date, you can continuously measure the urinary estriol in 24h. If it is always higher than 25mg, you can still wait under close observation; if it is less than 10mg, the fetus is at risk and should be subject to positive treatment.
Owing to lack of hypothalamus, non-brain child has pituitary hypoplasia and small adrenal gland. Since the supply of the raw material for the placental synthesis of estriol, 16-hydroxy isopropyl DHEA is in insufficient amount, the estriol in urine of pregnant women is very low with most being below the normal 10%.
The above information is edited by the lookchem of Dai Xiongfeng.
Purpose and Function
1. It can be used for treating cervicitis and especially suitable for treating menopausal syndrome and senile vaginitis.
2. It can also be used as the adjuvant drug for middle-term labor induction and artificial abortion. 3. It can also be used for treating prostatic hypertrophy and prostate cancer.
4. It still has a rapid role in increasing the peripheral leukocytes. It generally takes effect at 1 to 3 days after the treatment but with a short duration period. It also has efficacy in treating leukopenia caused by chemotherapy or radiotherapy.
5. It can be used for reducing the vascular permeability and fragility and can be used for the treatment of various kinds of hemorrhage. It also has quick hemostasis effect on menorrhagia, hysterectomy or tonsillectomy.
Precautions
1. Pregnant and lactating women, patients of breast hyperplasia, breast lumps, gynecological cancer, and aplastic anemia patients should be disabled with minor patients being not suitable for using it.
2. Patients of heart (liver, kidney) disease, hypertension, diabetes, epilepsy, migraine (including medical history), endometriosis, fibrocystic breasts, porphyria, hyperlipidemia or having history of pregnancy itching and herpes should take with caution.
3. If prescribed therapy doesn’t work, it is not suitable for increasing the dose or extending the usage time.
Drug Interactions
It can be used in combination with estradiol with competitive antagonism.
Storage
It should be sealed upon shading for storage.
Production method
Take estrone as raw material; go through acetylation, epoxidation, and reduction to obtain the estriol products.
Estrone [acetylation] → [16, 17-epoxidation] → [rearrangement] → [Restore] → [hydrolysis] → finished product of estriol.
Estrone acetate successively goes through followed enolization, acetylation, epoxidation and reduction to obtain it.
Hazard
A carcinogen (OSHA).
Synthesis
Estriol, estra-1,3,5(10)-trien-3,16α,17β-triol (28.1.25), is proposed to be synthesized
from the methyl ester of estrone (28.1.8). Methyl ester of estrone is reacted with isopropenylacetate
in the presence of p-toluenesulfonic acid, forming the corresponding
enolacetate (28.1.23). The resulting enolacetate is oxidized to an epoxide using perbenzoic
acid. The resulting epoxide (28.1.24) undergoes reduction by lithium aluminum hydride to.
Purification Methods
Crystallise estriol from EtOH/ethyl acetate. Also purify it by countercurrent distribution with cyclohexane/EtOAc (1:1) and EtOH/H2O (1:1). The UV (EtOH) has max at 280nm ( 2,090 M-1cm-1). [Huffmann & Lott 71 719 1949, Leeds et al. J Am Chem Soc 76 2943 1954, Beilstein 6 IV 7550.]
Check Digit Verification of cas no
The CAS Registry Mumber 50-27-1 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 0 respectively; the second part has 2 digits, 2 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 50-27:
(4*5)+(3*0)+(2*2)+(1*7)=31
31 % 10 = 1
So 50-27-1 is a valid CAS Registry Number.
InChI:InChI=1/C18H24O3/c1-18-7-6-13-12-5-3-11(19)8-10(12)2-4-14(13)15(18)9-16(20)17(18)21/h3,5,8,13-17,19-21H,2,4,6-7,9H2,1H3/t13?,14-,15?,16?,17+,18+/m1/s1
50-27-1Relevant academic research and scientific papers
STEREOSELECTIVE REDUCTION OF ALPHA-HYDROXYKETONE
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Page/Page column 10, (2012/03/27)
The present invention provides methods for 1, 2-asymmetric reduction of other compounds wherein 1,2- trans diol is present. In particular the present invention discloses preparation of 17β-Estriol and its derivatives having substantially free of 17α-Estriol impurity using an achiral reductant sodium triacetoxy borohydride.
Crystal structure of cytochrome P450 CYP105N1 from Streptomyces coelicolor, an oxidase in the coelibactin siderophore biosynthetic pathway
Lim, Young-Ran,Hong, Myoung-Ki,Kim, Jin-Kwang,Doan, Thanh Thi Ngoc,Kim, Dong-Hyun,Yun, Chul-Ho,Chun, Young-Jin,Kang, Lin-Woo,Kim, Donghak
, p. 111 - 117 (2013/02/23)
The genome sequence of Streptomyces coelicolor contains 18 cytochrome P450 enzymes. The recombinant CYP105N1 protein has been expressed in Escherichia coli and purified, and we report the biochemical and structural characterization of CYP105N1 from S. coelicolor. The purified protein exhibited the typical CO-binding spectrum of P450 enzymes and type I binding spectra with estradiol and a coelibactin analog. The oxidation of estradiol by CYP105N1, supported by H2O2, produced estriol. The crystal structure of CYP105N1 was determined at 2.9 ? resolution. An unexpected wide open binding pocket located above the heme group was identified, with a volume of approximately 4299 ?3. These results suggest that the large open pocket to the active site may be a key feature for easy access of the peptidyl carrier protein-bound substrate to perform the hydroxylation reaction. A molecular docking model with coelibactin showed that the phenyl group of coelibactin is located ? away from the heme-iron, suggesting that CYP105N1 may be involved in the hydroxylation of the phenyl ring of the coelibactin precursor during biosynthesis.
Estriol substantially free of 16alpha, 17alpha-estra-1,3,5(10)-triene-3,16,17-triol
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, (2008/06/13)
Estriol substantially free of 16α,17α-estra-1,3,5(10)-triene-3,16,17-triol, and process for obtaining the same.
Roles of cytochromes P450 1A2 and 3A4 in the oxidation of estradiol and estrone in human liver microsomes
Yamazaki, Hiroshi,Shaw, Peter M.,Guengerich, F. Peter,Shimada, Tsutomu
, p. 659 - 665 (2007/10/03)
Of seven cDNA-expressed human cytochrome P450 (P450) enzymes (P450s 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4) examined, P450 1A2 was the most active in catalyzing 2- and 4-hydroxylations of estradiol and estrone. P450 3A4 and P450 2C9 also catalyzed these reactions although to lesser extents than P450 1A2. P450 1A2 also efficiently oxidized estradiol at the 16α-position but was less active in estrone 16α-hydroxylation; the latter reaction and also estradiol 16α-hydroxylation were catalyzed by P450 3A4 at significant levels. Anti-P450 1A2 antibodies inhibited 2- and 4-hydroxylations of these two estrogens catalyzed by liver microsomes of some of the human samples examined. Estradiol 16α-hydroxylation was inhibited by both anti-P450 1A2 and anti-P450 3A4, while estrone 16α-hydroxylation was significantly suppressed by anti-P450 3A4 in human liver microsomes. Fluvoxamine efficiently inhibited the estrogen hydroxylations in human liver samples that contained high levels of P450 1A2, while ketoconazole affected these activities in human samples in which P450 3A4 levels were high. α- Naphthoflavone either stimulated or had no effect on estradiol hydroxylation catalyzed by liver microsomes; the intensity of this effect depended on the human samples and their P450s. Interestingly, in the presence of anti-P450 3A4 antibodies, α-naphthoflavone was found to be able to inhibit estradiol and estrone 2-hydroxylations catalyzed by human liver microsomes. The results suggest that both P450s 1A2 and 3A4 have major roles in oxidations of estradiol and estrone in human liver and that the contents of these two P450 forms in liver microsomes determine which P450 enzymes are most important in hepatic estrogen hydroxylation by individual humans. P450 3A4 may be expected to play a more important role for some of the estrogen hydroxylation reactions than P450 1A2. Knowledge of roles of individual P450s in these estrogen hydroxylations has relevance to current controversies in hormonal carcinogenesis.
Formylation of Oestrogens
Pert, Derek J.,Ridley, Damon D.
, p. 405 - 419 (2007/10/02)
Reimer-Tiemann formylations of oestradiol and oestrone were investigated and, whilst substitution was effected under certain conditions to give mixtures of 2-and 4-formyloestrogens, yields were very low and the method was unsuitable for preparative purposes.Regioselective methods were developed and 2-formyloestradiol was conveniently prepared from oestradiol by formylation of the lithio derivative of the bis(methoxymethyl) ether and removal of the protecting groups with the hydrochloric acid. 4-Formyloestradiol was prepared by a sequence of reactions starting with the methoxyethyl ether of 4-bromooestradiol, then metal-halogen interconversion, formylation with N-methylformanilide, and removal of the protecting group.A number of related derivatives, including 2-formyloestriol, were prepared.
Mechanistic Consideration of P-450 Dependent Enzymic Reactions: Studies on Oestriol Biosynthesis
Stevenson, David E.,Wright, J. Neville,Akhtar, Muhammad
, p. 2043 - 2052 (2007/10/02)
Methods for the synthesis of 19-hydroxy and 19-oxo derivatives of 16α-hydroxytestosterone have been developed.These compounds were labelled with 18O,2H and 3H at C-19 and also with 3H at C-17.The conversion of 3H>-16α,19-dihydroxytestosterone (11c) into oestriol (4c), using human placental aromatase was demonstrated in good yield and it was shown that in this process the 19-oxo compound (3c) is involved as an intermediate.The use of 16α,19-hydroxytestosterone, labelled with 3H predominantly in the HSi position, led to the conclusion that in oestriol biosynthesis the step, -CH2OH-> -CHO, is accompained by the loss of HRe and in the overall process the C-19 is ejected as HCOOH.On conducting experiments with either 18O2 or substrate containing 18O at C-19 it was shown that, in the conversion of 16α-hydroxy-19-oxotestosterone into oestriol, an atom of oxygen from O2 is incorporated into the formate.These features are similar to those already established for the corresponding biosynthesis of oestrone/oestradiol from androstenedione/testosterone.Our previous postulate that in oestrogen biosynthesis the same enzyme is involved in the hydroxylation reaction, -CH3 -> -CH2OH, and in the conversion, -CH2OH -> -CHO, as well as in the final cleavage of the C-10-C-19 bond is further developed.Attention is drawn to the fact that, if cytochrome P-450 dependent reactions are viewed to occur via a radical mechanism, then a concept can be developed which unifies the wide variety of transformations catalysed by this group of enzymes.The diversity of reactions would then arise from the alternative mode of decomposition of radical species by one or a combination of the following processes: (a) hydrogen abstraction; (b) disproportionation; (c) fragmentation; and (d) association of radicals.
Partial Purification and Characterization of Two β-Glucoronidases from Alcaligenes NG-11
Ogushi, Susumu,Koga, Satoshi,Ito, Kiyoshi,Makino, Yasutaka,Ando, Makoto,Tsuru, Daisuke
, p. 3093 - 3100 (2007/10/02)
A strain of Alcaligenes isolated from soil was a good producer of β-glucuronidase, and the enzyme was purified from the cell-free extract by sequential column chromatography on DEAE-Toyopearl, Toyopearl HW-55F, and Phenyl-Sepharose CL-4B.By these procedures, two β-glucuronidases designated as β-glucuronidases I and II were purified 240- and 508-fold, respectively. β-Glucuronidase I, with a molecular weight of 75,000, had an optimum pH at 7.5 and the enzyme II, with a molecular weight of 300,000, and maximum activity at pH 6.0.Both enzymes were strongly inhibited by saccharo-1,4-lactone, glucaro-δ-lactam, p-chloromercuribenzoate, Hg2+, and N-bromosuccinimide. β-Glucuronidase I was active toward estrogen-3-β-glucuronides and inert toward β-glucuronide conjugates of menthol, estrogen-17β-, estrogen-16α-, androsterone-3α-, testosterone-17β-, cortisol-17α-. β-Glucuronidase II hydrolyzed all of these substrates. β-Glucuronidase I was inhhibited by phenolphthalein and its glucuronide.
Synthesis of 2-Methoxy- and 4-Methoxy-Estrogens with Halogen-Methoxy Exchange Reaction
Numazawa, Mitsuteri,Ogura, Yuko,Kimura, Katsuhiko,Nagaoka, Masao
, p. 3701 - 3715 (2007/10/02)
Synthesis of 2-methoxy- and 4-methoxy-estrone (6) and (9), 2-methoxy- and 4-methoxy-estradiol (15) and (18), and 2-methoxy- and 4-methoxy-estratriol (24) and (27) are described.Catalytic hydrogenation over Pd/C of 2,4-dibromo or 2,4-diiodo estrogens gave regioselectively the corresponding 4-halogeno derivatives in excellent yields.Reaction of 2-iodo or 4-iodo estradiol and 2-iodo or 4-iodo estriol with NaOCH3 in MeOH and dimethylformamide (DMF) in the presence of CuCl2 gave in an excellent yield and in a good yield, while (6) and (9) were also similarly obtained by the reaction with pyridine instead of DMF.
IDENTIFICATION OF 6α- AND 7α-HYDROXYESTRONE AS MAJOR METABOLITES OF ESTRONE AND ESTRADIOL IN PORCINE UTERUS
Maschler, I.,Ball, P.,Bayerkoehler, G.,Gaues, J.,Knuppen, R.
, p. 597 - 608 (2007/10/02)
Polar metabolites extracted from the effluents of viable porcine uterine strips superfused with either 6,7-3H-estrone or 6,7-3H-estradiol were identified as a 1 : 1 mixture of 6α-hydroxyestrone and 7α-hydroxyestrone by paper chromatography in various systems, derivatization and crystallizations to a constant specific activity.The hydroxylated compounds are the only derivatives detected after estrone superfusion.The major metabolite of estradiol released in short-time experiments is estrone followed by its 6α- and 7α-hydroxylated derivatives.
