二茂铁羧酸、醇、酯的合成及细胞毒活性研究
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摘要
二茂铁及其衍生物均具有较强的抗癌活性,目前已被广泛地应用于药物合成及临床应用上。本文主要研究碳链对二茂铁活性的影响,并对其构效关系进行了分析。基于此,本文包括如下三方面的内容：
1.为了进行结构与性质的研究,首先需要合成一系列的二茂铁羧酸(1a～6a)、醇酚类(1b～8b)、酯(1c～8c)。(1)在合成过程中,鉴于传统的Suzuki反应存在的弊端和不足,通过改进Suzuki反应,以较高的收率合成了二种二茂铁醇6b和7b,该方法的中间产物二茂铁硼酸极易制得,操作简便且毒性小,因此Suzuki反应是一种将二茂铁基引入其它物质的非常便捷的新型方法。(2)通过Mitsunobu反应合成了二茂铁基异维A酸酯(1c～8c)八种产物。Mitsunobu反应既继承了DCC/DMAP法反应条件温和、构型保持的优点,又克服了反应需时长,副产物多,产物难以分离的缺点。
2.通过比较三种主要的测试体外细胞毒活性的方法,MTT法以其快速简便,不需要特殊检测仪器、无放射性同位素、灵敏度高、经济的特点而得到本文作者的采用。并将所合成的二茂铁羧酸(1a～6a)、醇(1b～5b)、酯(1c～8c),采用MTT法测试它们及异维A酸共20种对肺癌细胞(A549)、肝癌细胞(BEL7404)和舌癌细胞(Tca)的细胞毒活性。结果显示：二茂铁羧酸、醇、酯均有抗癌活性且有一定的规律性。
3.根据所测得的毒活性数据,对二茂铁羧酸、醇、酯的构效关系进行了分析和探讨。(1)同类化合物由于其取代基及取代位置的不同而导致其生物活性完全不同。(2)二茂铁羧酸、醇,异维A酸及其酯对癌细胞都有一定的抗癌活性,其中碳链的长短、芳环、羰基、电子效应、基团的亲水疏水性、空间效应都对抗癌活性有一定的影响。(3)不同类化合物体现出了不一样的抗癌活性：二茂铁羧酸优于二茂铁醇优于二茂铁异维A酸及酯。
Ferrocene and its derivatives have strong anti-cancer activity. At present, they have been used widely in the field of pharmaceutical synthesis and clinical applications. This paper studies the carbon chain on the activity of ferrocene and analyzes its structure-activity relationship. Based on this, Three parts are contained in this article as follows:
1. In order to study the structure and properties, we first need to synthesize series of ferrocene carboxylic acid (la～6a), alcohol-phenol (1b～8b), ester (1c～8c). (1)In the process of synthesis, the Suzuki reaction in view of the traditional drawbacks and deficiencies, improved the Suzuki reaction, a higher yield synthesis of the two kinds of ferrocene alcohols 6b and 7b. It is the method of the intermediate products of ferrocene boric acid because of easily obtained, simple and low toxicity. So, it is very convenient way of Suzuki reaction to the introduction of other ferrocenyl new material. (2) They was synthesized to the eight products of ferrocenyl esters of 13-cis-Retinoic Acid (lc～8c) by Mitsunobu reaction. Mitsunobu reaction not only inherite the advantage of the DCC/DMAP method which is mild reaction conditions can maintain the advantages of configuration, but also overcome the reaction defects of long times, multi-product, difficult to separate the product.
2. By comparing the three main test methods of vitro cytotoxicity, MTT method is used because of its fast and simple, no special test equipment, no radioactive, sensitive, and economic characteristics. We test cytotoxic activities of twenty kinds of the synthesis of ferrocene carboxylic acid (la～6a), alcohol (1b～5b), ester (1c～8c) and 13-cis-Retinoic Acid on lung cancer cells (A549), hepatoma cells (BEL7404) and tongue cancer cells (Tca) using MTT method. According to the data of drug activity by MTT method, we calculat the IC50 value.The results show that:ferrocene carboxylic acids, alcohols, esters have anti-cancer activity and a certain regularity.
3. Their structure-activity relationships are analysized and discussed according to the measured data of cytotoxic activity of ferrocene carboxylic acids, alcohols, esters. (1) There is entirely different biological activity that the similar compounds because of its substituents and substituted positions. (2) The cancer cells have certain anti-cancer activity for ferrocene carboxylic acid, alcohol, ester and 13-cis-Retinoic Acid. The factors affecting on the anti-tumor activity includ the length of carbon chain, aromatic, carbonyl, electronic effects of hydrophobic and hydrophilic groups space effect. (3) Different types of compounds reflect the different anti-cancer activity:ferrocene carboxylic acid is superior to ferrocene alcohol that is better than ferrocene ester and 13-cis-Retinoic Acid.
1.为了进行结构与性质的研究,首先需要合成一系列的二茂铁羧酸(1a～6a)、醇酚类(1b～8b)、酯(1c～8c)。(1)在合成过程中,鉴于传统的Suzuki反应存在的弊端和不足,通过改进Suzuki反应,以较高的收率合成了二种二茂铁醇6b和7b,该方法的中间产物二茂铁硼酸极易制得,操作简便且毒性小,因此Suzuki反应是一种将二茂铁基引入其它物质的非常便捷的新型方法。(2)通过Mitsunobu反应合成了二茂铁基异维A酸酯(1c～8c)八种产物。Mitsunobu反应既继承了DCC/DMAP法反应条件温和、构型保持的优点,又克服了反应需时长,副产物多,产物难以分离的缺点。
2.通过比较三种主要的测试体外细胞毒活性的方法,MTT法以其快速简便,不需要特殊检测仪器、无放射性同位素、灵敏度高、经济的特点而得到本文作者的采用。并将所合成的二茂铁羧酸(1a～6a)、醇(1b～5b)、酯(1c～8c),采用MTT法测试它们及异维A酸共20种对肺癌细胞(A549)、肝癌细胞(BEL7404)和舌癌细胞(Tca)的细胞毒活性。结果显示：二茂铁羧酸、醇、酯均有抗癌活性且有一定的规律性。
3.根据所测得的毒活性数据,对二茂铁羧酸、醇、酯的构效关系进行了分析和探讨。(1)同类化合物由于其取代基及取代位置的不同而导致其生物活性完全不同。(2)二茂铁羧酸、醇,异维A酸及其酯对癌细胞都有一定的抗癌活性,其中碳链的长短、芳环、羰基、电子效应、基团的亲水疏水性、空间效应都对抗癌活性有一定的影响。(3)不同类化合物体现出了不一样的抗癌活性：二茂铁羧酸优于二茂铁醇优于二茂铁异维A酸及酯。
Ferrocene and its derivatives have strong anti-cancer activity. At present, they have been used widely in the field of pharmaceutical synthesis and clinical applications. This paper studies the carbon chain on the activity of ferrocene and analyzes its structure-activity relationship. Based on this, Three parts are contained in this article as follows:
1. In order to study the structure and properties, we first need to synthesize series of ferrocene carboxylic acid (la～6a), alcohol-phenol (1b～8b), ester (1c～8c). (1)In the process of synthesis, the Suzuki reaction in view of the traditional drawbacks and deficiencies, improved the Suzuki reaction, a higher yield synthesis of the two kinds of ferrocene alcohols 6b and 7b. It is the method of the intermediate products of ferrocene boric acid because of easily obtained, simple and low toxicity. So, it is very convenient way of Suzuki reaction to the introduction of other ferrocenyl new material. (2) They was synthesized to the eight products of ferrocenyl esters of 13-cis-Retinoic Acid (lc～8c) by Mitsunobu reaction. Mitsunobu reaction not only inherite the advantage of the DCC/DMAP method which is mild reaction conditions can maintain the advantages of configuration, but also overcome the reaction defects of long times, multi-product, difficult to separate the product.
2. By comparing the three main test methods of vitro cytotoxicity, MTT method is used because of its fast and simple, no special test equipment, no radioactive, sensitive, and economic characteristics. We test cytotoxic activities of twenty kinds of the synthesis of ferrocene carboxylic acid (la～6a), alcohol (1b～5b), ester (1c～8c) and 13-cis-Retinoic Acid on lung cancer cells (A549), hepatoma cells (BEL7404) and tongue cancer cells (Tca) using MTT method. According to the data of drug activity by MTT method, we calculat the IC50 value.The results show that:ferrocene carboxylic acids, alcohols, esters have anti-cancer activity and a certain regularity.
3. Their structure-activity relationships are analysized and discussed according to the measured data of cytotoxic activity of ferrocene carboxylic acids, alcohols, esters. (1) There is entirely different biological activity that the similar compounds because of its substituents and substituted positions. (2) The cancer cells have certain anti-cancer activity for ferrocene carboxylic acid, alcohol, ester and 13-cis-Retinoic Acid. The factors affecting on the anti-tumor activity includ the length of carbon chain, aromatic, carbonyl, electronic effects of hydrophobic and hydrophilic groups space effect. (3) Different types of compounds reflect the different anti-cancer activity:ferrocene carboxylic acid is superior to ferrocene alcohol that is better than ferrocene ester and 13-cis-Retinoic Acid.
引文
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