每周分子 | Molecule of the Week

Original ACS 美国化学会 ACS美国化学会 2022-07-01

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每周分子：雌四醇

Molecule of the Week: Estetrol

雌四醇，又称E4，是一种类固醇激素，与雌激素家族中的性激素密切相关，相关的性激素中包括之前介绍的每周分子雌二醇。与雌二醇和其他激素一样，雌四醇在妊娠早期出现在胎儿的肝脏中，并在母亲体内“在妊娠期间其浓度呈指数级增长”。雌四醇在胎儿中的浓度≈在母体中浓度的10倍。

1965年，卡罗林斯卡学院(Karolinska Institute，位于瑞典斯德哥尔摩)的Egon Diczfalusy和他的同事们在对婴儿期早期雌二醇代谢的研究中发现了雌四醇。但是Diczfalusy当时并没有意识到雌四醇可能是一种很有价值的药物；它在之后的35年间几乎没有引起太多的重视。

2000年，任职于荷兰避孕药具制造商Organon的Herjan Coelingh Bennink认识到了雌四醇在孕妇和胎儿体中的存在，认为应该探索其是否为一种安全的治疗药物。Bennink创立的Pantarhei Bioscience公司(位于荷兰Zeist)及后来的Mithra Pharmaceuticals公司(位于比利时列日市)对雌四醇作为口服避孕药的研究表明，它与当时的主导产品炔雌醇一样有效，而且没有跟炔雌醇一样的副作用。

Mithra Pharmaceuticals公司进行了一项联合使用雌四醇和屈螺酮的临床试验，屈螺酮是一种通常包含在雌激素类避孕药中的孕激素。2021年，美国FDA批准了商品名为Estelle的雌四醇-屈螺酮的复方药物。它是由Mayne Pharma公司销售的，这是一家在美国北卡罗来纳州设有机构的澳大利亚公司。

雌四醇很难合成。商业化的生产方法是从一种大豆衍生的植物甾醇起始反应，并且共需8个合成步骤。Mithra Pharmaceuticals公司最近宣布，他们已选择Seqens(位于法国Écully)拥有129年历史的工厂(位于法国新城-拉加伦, Villeneuve-la-Garenne)来生产雌四醇。

雌四醇信息速览

CAS 登记号	15183-37-6
CAS SciFinder命名	Estra-1,3,5(10)-triene-3,15,16,17-tetrol, (15α,16α,17β)-
分子式	C₁₈H₂₄O₄
摩尔质量	304.38 g/mol
外观	白色晶体或粉末
熔点	244 °C
水溶性	1.4 g/L

雌四醇危害信息

GHS分类：急性毒性，口服，分类5
H303-吞食可能有害
GHS分类：致癌性，分类2
H351-疑似致癌
GHS分类：生殖毒性，分类1B
H360-可能会损害生育能力或未出生婴儿
GHS分类：短期(急性)水生危害，分类3
H402-对水生生物有害
GHS分类：长期(慢性)水生危害，分类3
H412-对水生生物有害，具有长期影响

【关于每周分子】

自2001年以来，“每周分子”已成为广受欢迎的栏目。多数分子由读者推荐。每个结构都经由科学家审查，并以3-D和平面图像的形式显示，同时附有该分子简介。可以通过美国化学文摘社 (CAS) 提供的CAS SciFinderⁿ中的CAS REGISTRY获取“每周分子”的更多信息。CAS REGISTRY中的每条物质信息都展示了物质的CAS登记号、索引名、通用名、商品名、书目信息等其他更多信息。发送邮件至motw@acs.org推荐您感兴趣的分子吧。

Estetrol, also called E4, is a steroid hormone closely related to sex hormones in the estrogen family, including former Molecule of the Week estradiol. Along with estradiol and other hormones, estetrol occurs in the fetal liver during early pregnancy and in the mother in “exponentially growing concentrations during gestation”. Fetal concentrations are ≈10 times higher than maternal concentrations.

Estetrol was discovered in 1965 by Egon Diczfalusy and colleagues at the Karolinska Institute (Stockholm) during a study of the metabolism of estradiol in early infancy. But Diczfalusy did not realize at the time that estetrol could be a valuable drug; it was largely ignored for 35 years.

In 2000, Herjan Coelingh Bennink at the Dutch contraceptive manufacturer Organon, recognizing estetrol’s occurrence in pregnant women and fetuses, believed that it should be explored as a safe therapeutic agent. Studies on estetrol as an oral contraceptive at Bennink-founded Pantarhei Bioscience (Zeist, The Netherlands) and later at Mithra Pharmaceuticals (Liège, Belgium) demostrated that it is as effective as the leading product, ethinylestradiol, without its adverse side effects.

Mithra conducted clinical trials on a combination of estetrol and drospirenone3, a progestin commonly included in estrogen-based contraceptives. In 2021, the estetrol–drospirenone combination, tradenamed Estelle, was approved by the US Food and Drug Administration. It is marketed by Mayne Pharma, an Australian company with facilities in North Carolina.

Estetrol is difficult to synthesize. The commercial manufacturing method begins with a soy-derived phytosterol and requires eight synthetic steps. Mithra recently announced that it chose Seqens (Écully, France) to produce estetrol at its 129-year-old manufacturing plant in Villeneuve-la-Garenne, France.

Estetrolfast facts

CAS Reg. No.	15183-37-6
SciFinder nomenclature	Estra-1,3,5(10)-triene-3,15,16,17-tetrol, (15α,16α,17β)-
Empirical formula	C₁₈H₂₄O₄
Molar mass	304.38 g/mol
Appearance	White crystals or powder
Melting point	244 °C
Water solubility	1.4 g/L

Estetrolhazard information

Acute toxicity, oral, category 5
H303-May be harmful if swallowed
Carcinogenicity, category 2
H351-Suspected of causing cancer
Reproductive toxicity, category 1B
H360-May damage fertility or the unborn child
Short-term (acute) aquatic hazard, category 3
H402-Harmful to aquatic life
Long-term (chronic) aquatic hazard, category 3
H412-Harmful to aquatic life with long-lasting effects

About Molecule of the Week

MOTW has been a popular feature on ACS website since 2001. Many molecules are suggested by our website visitors. Every structure is reviewed by a scientist and displayed in 3-D and flat images with a brief description. Each week’s molecule also links to a sample record from the CAS REGISTRY, which is searched using CAS SciFinderⁿ. Each record displays the registry number, index name and synonyms, bibliographic information, and more. Send us a molecule suggestion at motw@acs.org.

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