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1、手性药物和它的未来在听了王梅祥老师的课之后,我对手性产生了非常大的兴趣。手性是自然界中广泛存在的现象,是自然界的本质属性之一。如果一个物体不能与其镜像重合,那么这个物体就称为手 性物体。作为生命活动重要基础的生物大分子,如蛋白质、多糖、核酸和酶等,几乎全是手 性的,这些分子在体内往往具有重要生理功能。手性的研究是目前化学领域最热门的话题之 一,而手性药物的研发也是未来医药的发展方向。手性药物是指药物分子结构中引入手性中心后,得到的一对互为实物与镜像的对映异构体。这些对映异构体的理化性质基本相似,仅仅是旋光性有所差别,分别被命名为R-型(右旋) 或S-型(左旋)、外消旋。在生物体系中,立体异构识
2、别是极明显的。一般就手性药物分子 而言,可能四种不同的行为:(1)只有一种异构体具有所希望的活性,另一种没有显著活性。(2)两种对映体都具有等同的或者近似等同的定性和定量的生物活性。(3)两种对映体具有定量上等同但定性上不同的活性。(4)各对映体具有定量上不同的活性。更通俗地说,两 种对映体的性质可能相同也可能不同,效力也有大有小,有的对映体对治疗疾病有益,其他 的对映体可能非但无益甚至有害。在老师讲到的“沙利度胺悲剧”中,原本的镇静剂之所以能够导致畸形婴儿的出生,正是因为在其中含有S-对应异构体,而这种异构体具有强烈的致畸性,因而导致了悲剧的发生。今天,手性药物的开发已经进入一个相对成熟的阶
3、段,更展现出蓬勃发展的态势。类似于 几十年前“沙利度胺”的悲剧也应该不会有再次发生的可能了。目前世界上使用的药物总数 约为 1900 种手性药物占50%以上,在临床常用的 200 种药物中,手性药物多达114 种。全 球2001年以单一光学异构体形式出售的市场额达到1 472亿美元,相比于2000年的1 330 亿美元增长了 10%以上。预计手性药物到2010年销售额将达到2 000 亿美元。手性药相比于平面药物而具有非常大的优势。正如前面所说,对于手性药物,一个异构体 可能是有效的,而另一个异构体可能是无效甚至是有害的。手性制药就是利用化合物的这种 原理,开发出药效高、副作用小的药物。在临床
4、治疗方面,服用对映体纯的手性药物不仅可 以排除由于无效对映体所引起的毒副作用,还能减少药剂量和人体对无效对映体的代谢负担, 对药物动力学及剂量有更好的控制,提高药物的专一性。当然,鉴于手性药物两种不同的对应异构体可能具有的截然不同的生物效应,人们对手性药物的用药安全一直高度重视。近年来许多国家的药政部门对手性药物的开发、专利申请及 注册做出了相应的规定。FDA就规定,对于有手性因素的药物倾向于发展单一对映体的产品,对申请的消旋体药,则要求将两个对映体的详细生活理性、毒性数据分别提供,不得视为相同物质。尽管在手性药物的使用上还存在许多问题有待解决,但手性药物的不断研发是大势所趋, 也是制药业将来
5、的潜力所在。目前人类还有许多尚待攻克的疾病,如癌症、艾滋病等,手性 药物的开发将会为人类最终攻克这些疾病提供巨大的支持。2006年5 月26日美国食品与 医药管理局(FDA)批准了 Celgene公司要求加快审批的沙利度胺和地塞米松联用治疗新 诊断的多发性骨髓瘤患者的申请。相信越来越多的手性药物将会为我们的生活保驾护航。虽然手性药物的使用有一定的危险性,但这种危险性是可以控制的,而手性药物的其他优 势决定了它的光明的发展前景。希望这种曾经造成悲剧的药物能够为人类减少一些痛苦,带 来活力和快乐。附:SCI检索结果1.题目:Direct HPLC enan tioseparati on of om
6、eprazole and its chiral impurities: applicati on to the determination of enantiomeric purity of esomeprazole magnesium trihydrate.作者: Zanitti, Leo; Ferretti, Rosella; Gallinella, Bruno; La Torre, Francesco; Sanna, Maria Luisa; Mosca, Antonina; Cirilli, Roberto摘要: Analytical and semipreparative high-
7、performance liquid chromatography (HPLC) enantioseparation of the proton-pump inhibitor omeprazole (OME) and its potential organic chiral impurities were accomplished on the immobilised-type Chiralpak IA chiral stationary phase (CSP) under both polar organic and normal-phase conditions. The (S)-enan
8、tiomers were isolated with a purity of 99% ee and their absolute configuration was empirically assigned by circular dichroism (CD) spectroscopy. A chemo- and enantioselective HPLC method was validated to control the enantiomeric purity of the (S)-enantiomer of OME (ESO), an active ingredient contain
9、ed in drug products, in the presence of chiral and achiral related substances. The precision, linearity and accuracy of the determination of the (R)-impurity as well as the recovery of ESO from a pharmaceutical preparation were determined. The proposed method uses the mixture methyl tert-butylether
10、(MtBE)-ethyl acetate (EA)-ethanol (EtOH)-diethylamine (DEA)60:40:5:0.1 (v/v/v/v) as a mobile phase. In these conditions, linearity over the concentration range 0.5-25 microg/ml for (R)-enantiomer was obtained. The limits of detection and quantification were 99 and 333 ng/ml, respectively. The intra
11、and inter-day assay precision was less than 2% (RSD%). 2010 Elsevier B.V. All rights reserved.2.题目:Enantioselective quantification of carvediloI in human plasma by HPLC in heavily medicated heart failure patients作者: Zakrzewski-Jakubiak M (Zakrzewski-Jakubiak, Marcin), de Denus S (de Denus, Simon), L
12、eblanc MH (Leblanc, Marie-Helene), White M (White, Michel)2, Turgeon J (Turgeon, Jacques)摘要: A simple, specific, sensitive, inexpensive and rapid HPLC method for enantioselective quantification of carvedilol in human plasma was developed in this study. S(-)- and R(+)-carvedilol and R(+)-propranolol
13、as the internal standard were extracted from human plasma by liquid-liquid extraction using methyl tert-butyl ether. Enantioseparation was performed on a reverse-phase C18 Phenomenex Luna 5micron 150 mm x 2 mm column after chiral derivatization with 2,3,4,6 tetra O acetyl beta-D-glucopyranosyl isoth
14、iocyanate. The mobile phase was a mixture of water and acetonitrile. The peaks were detected using a fluorescence detector, where the excitation and emission wavelengths were set at 242 and 344 nm, respectively. The limits of quantification for the S(-)- and R(+)-carvedilol enantiomers were both 0.5
15、 ng/ml. Combined intra- and inter-day variations for both enantiomers were less than 8.3%. The combined accuracy for both enantiomers ranged from 91.7 to 104.7%. This method was used to assay the carvedilol enantiomers in human plasma samples obtained from heavily medicated heart failure patients wi
16、thin the framework of a clinical trial. (C) 2010 Elsevier B.V. All rights reserved.3. 题目: Stereoselective and Multiple Carrier-Mediated Transport of Cetirizine AcrossCaco-2 Cell Monolayers with Potential Drug Interaction作者: He, Y (He, Ying) , Liu, Y (Liu, Yao), Zeng, S (Zeng, Su)摘要: The aim of this study was to explore potential transport mechanisms of cetirizine enantiomers across Caco-2 cells. Cetirizine displayed polarized transport at