17β-雌二醇和17α-炔雌二醇3-醚化合物的合成及其药理活性的研究
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摘要
雌激素类化合物的研究已有几十年的历史,有一定的生物效价,但往往由于雌活力高、副作用大而使应用受到限制。雌激素类化合物对放射损伤有较好的预防和治疗作用。雌激素作为抗放药物的研究国内外已有近60年的历史,但因其有较强的雌活力和对胃肠、肝脏产生不良影响和毒副作用,以及使子宫基底膜增厚的副作用而怀疑其潜在的致癌活性,使其在相关领域的应用受到限制。雌激素的抗放效果与雌激素的化学结构类型有着密切的关系。因此在抗放射病药物研究的过程中,如何寻找一个有关雌激素结构的同系物,使其既有较强的抗放效果,而又有较低的毒副作用,仍是雌激素类抗放药物研究工作的重要内容。
为了找到一种抗放效价高,毒副作用小的雌激素类抗放药物,本课题对乙炔雌二醇和雌二醇进行了结构改造,设计并合成了乙炔雌二醇-3-烯丙基醚(ES-1)、雌二醇-3-烯丙基醚(ES-2)、乙炔雌二醇-3-异戊烯基醚(ES-3)和雌二醇-3-异戊烯基醚(ES-4)四个化合物,合成步骤简短,产率较高,反应条件不苛刻,原料常见易得,适合工业化生产,可以在此基础上继续进行工业化生产工艺的研究。本课题还对合成的四个雌激素衍生物进行了MS、IR、~1H-NMR和~13C-NMR等光谱学的鉴定并确证了其结构。同时对四个化合物进行了抗放生物效价、改善造血功能效价等药效学实验的研究,实验结果表明雌二醇-3-烯丙基醚(ES-2)和雌二醇-3-异戊烯基醚(ES-4)两个化合物对射线引起的白细胞低下有显著的升白作用,具有进一步研究开发的价值。
The research of estrogens has several decades of history, and it has a certain degree of biological potency, but its application is limited often due to the high activity of estrogen and the serious side effects. Estrogens has the better prevention and treatment to the radiation injury. As an anti-radiation drug, the study of estrogens has nearly 60 years history at home and abroad, but often due to its strong activity of estrogen and side-effects on the stomach intestine and the liver, as well as suspecting its potential carcinogenic activity because of the side effect of thickening uterine basement membrane, its application is limited in the relevant areas. The anti-radiation effect of estrogens has a close relationship with the chemical structure of estrogens. So in the course of the study on the anti-radiation drug, how to find a homologue of estrogen, which has stronger anti-radiation effect and less side effects, is still an important part of the research on the anti-radiation drug of estrogens.
In order to find an anti-radiation drug of estrogens which has high anti-radiation effect and low harmful side-effects, we decide to choice estradiol and ethinylestradiol as leading compounds and transform the chemical structure of the both compounds through method of synthesis. Four compounds have been designed and synthesized and they are estradiol-3-allyl ether、ethinylestradiol-3-allyl ether、estradiol-3-isopentenyl ether and ethinylestradiol-3-isopentenyl ether. The steps of synthesis is short, the yield is high, the conditions of reaction are not very harsh, and the raw materials for reaction are also easy to get, so it is suitable for industrial production and valuable to continue to further research on the technology of industrial production. The chemical structures of the four new estrogen derivatives were confirmed by MS, IR, ~1H-NMR and ~(13)C-NMR.
The pharmacological experiments of anti-radiation biological potency and improving the function of blood potency of the four new compounds have been done. The experimental results showed that estradiol-3-allyl ether and estradiol-3-isopentenyl ether have significant effect of improving the number of white blood cells which is decreased by ray, and so it is very valuable to further study.
为了找到一种抗放效价高,毒副作用小的雌激素类抗放药物,本课题对乙炔雌二醇和雌二醇进行了结构改造,设计并合成了乙炔雌二醇-3-烯丙基醚(ES-1)、雌二醇-3-烯丙基醚(ES-2)、乙炔雌二醇-3-异戊烯基醚(ES-3)和雌二醇-3-异戊烯基醚(ES-4)四个化合物,合成步骤简短,产率较高,反应条件不苛刻,原料常见易得,适合工业化生产,可以在此基础上继续进行工业化生产工艺的研究。本课题还对合成的四个雌激素衍生物进行了MS、IR、~1H-NMR和~13C-NMR等光谱学的鉴定并确证了其结构。同时对四个化合物进行了抗放生物效价、改善造血功能效价等药效学实验的研究,实验结果表明雌二醇-3-烯丙基醚(ES-2)和雌二醇-3-异戊烯基醚(ES-4)两个化合物对射线引起的白细胞低下有显著的升白作用,具有进一步研究开发的价值。
The research of estrogens has several decades of history, and it has a certain degree of biological potency, but its application is limited often due to the high activity of estrogen and the serious side effects. Estrogens has the better prevention and treatment to the radiation injury. As an anti-radiation drug, the study of estrogens has nearly 60 years history at home and abroad, but often due to its strong activity of estrogen and side-effects on the stomach intestine and the liver, as well as suspecting its potential carcinogenic activity because of the side effect of thickening uterine basement membrane, its application is limited in the relevant areas. The anti-radiation effect of estrogens has a close relationship with the chemical structure of estrogens. So in the course of the study on the anti-radiation drug, how to find a homologue of estrogen, which has stronger anti-radiation effect and less side effects, is still an important part of the research on the anti-radiation drug of estrogens.
In order to find an anti-radiation drug of estrogens which has high anti-radiation effect and low harmful side-effects, we decide to choice estradiol and ethinylestradiol as leading compounds and transform the chemical structure of the both compounds through method of synthesis. Four compounds have been designed and synthesized and they are estradiol-3-allyl ether、ethinylestradiol-3-allyl ether、estradiol-3-isopentenyl ether and ethinylestradiol-3-isopentenyl ether. The steps of synthesis is short, the yield is high, the conditions of reaction are not very harsh, and the raw materials for reaction are also easy to get, so it is suitable for industrial production and valuable to continue to further research on the technology of industrial production. The chemical structures of the four new estrogen derivatives were confirmed by MS, IR, ~1H-NMR and ~(13)C-NMR.
The pharmacological experiments of anti-radiation biological potency and improving the function of blood potency of the four new compounds have been done. The experimental results showed that estradiol-3-allyl ether and estradiol-3-isopentenyl ether have significant effect of improving the number of white blood cells which is decreased by ray, and so it is very valuable to further study.
引文
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