制药工程 专业英语 Unit 21

单击此处编辑母版文本样式,第二级,第三级,*,单击此处编辑母版标题样式,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,制药工程 专业英语 Unit 21,概念简介,手性药物,:,具有手性结构及药理活性的具有治疗疾病作用的手性化合物。,药理作用：,通过其余体内大分子进行手性识别和匹配产生活性而起到治疗的作用。一对对映体的手性药物在手性结构上的差异往往会导致它们在药理活性、药物代谢及毒性等方面产生不同的体内的药理活性。,根据一对对映体的手性药物药理作用和药效，可分为：,一个有药理活性，而它的对映体没有药理活性；,一对对映体有相反的药理活性，一个有活性，对映体甚至可能显毒性；,一对对映体药理活性相同，但有差别；,一对对映体有迥乎不同的药理活性；,一对对映体药理活性完全相同。,2,Words,encompass,chirality (a. chiral),enantiomer,diastereomer,mesomer,racemate,unwanted,clear-cut,tolerability,impetus,building block,cholesterol,menthol,stationary/,mobile,phase,assay,chiral selector,tartaric acid,ensuing,embryos,counter,clockwise,vt.,包含；包围，环绕,n.,手,(,征,),性,(a.,手,(,征,),性的,),n.,对映,(,异构,),体,n.,非对映,(,异构,),体,n.,内消旋体,n.,外消旋体,(,化合物,),a.,有害的；不需要的,a.,清晰的；轮廓鲜明的,n.,耐受性,;,容忍度,n.,动力；促进；冲力,n.,砌块；积木；构件,n.,胆固醇；胆甾醇,n.,薄荷醇，薄荷脑,固定相,/,流动相,n.,化验，试验；,vt.,分析，测试,手性选择试剂,酒石酸,a.,跟着发生的,n.,胚胎；晶胎,adv.,逆,时针地,手性几乎并不是化学中的新概念，但在过去的几年里手性技术的进步已对制药研究和开发产生了越来越大的影响。如今，手性技术对合理的药物设计正起着强大的影响。,Chirality is hardly a new concept in chemistry, yet advances in chiral technology have had a growing impact on pharmaceutical research and development over the past few years. Chiral technology now exerts a strong influence on rational drug design.,尤其在寻求高选择性作用（机制）时，手性技术有助于新受体为基础的或酶抑制的小分子药物,的构思（概念的形成）,和发现。手性技术被人们所认可主要是因为现在已有大量可用于制造单一对映体手性药物的技术。,It aids the,conception,and discovery of new receptor-based or enzyme-inhibiting small molecule drugs, especially where high selectivity of action is sought. Its acceptance is largely because there is now an abundance of technology in place for the manufacture of single-enantiomer chiral drugs.,对那些不熟悉手性技术的人们而言，,该术语,包括生产单一手性形式,(,对映体,),化合物的技术，具有足够复杂性的分子结构的化合物是手性的；也就是说，这时分子不能与其镜像叠加,(,重合,),。随着分子变得更加复杂，药品的特异作用性增加；对更具特异性作用的药品的追求将导致更大比例的药品为手性。,For those unfamiliar with chiral technology,the term,encompasses the range of techniques for producing the single-handed forms (enantiomers) of compounds that have sufficient molecular complexity to be chiral, that is, when molecules cannot be superimposed on their mirror images. Since the specificity of drugs increases as the molecules become more complex, the drive for more specific drugs will lead to a greater proportion being chiral.,如果某一药物是手性的，在生物学范畴里其对映体总具有不同的活性。一种药物可能会与细胞受体发生特异性的相互作用而产生期望的结果，而另外一种药物则可能产生无用的作用，或通过某些其他的相互作用而可能导致有害的作用。,If a drug is chiral, then in biological terms the enantiomers invariably differ in activity. One may specifically interact with a cell receptor to produce the desired outcome while the other might have no useful application or might have an unwanted effect through some other interaction.,在明确的例子中，手性化合物的一个异构体是“对人体有益的”，而另一个异构体则是“对人体有害的”，发展单一异构体的药物以加强其安全性和耐受性，可以获得显而易见的利润。此外，这也可以通过监管渠道加快药品的发展，从而节省研发成本。,In the clear-cut example where one isomer of a chiral compound is good and the other bad, there is obvious benefit from developing the drug as the single isomer to enhance its safety and tolerability. In addition, this can also speed the progress of the drug through regulatory channels, thereby saving R&D costs.,虽然过去的许多已开发的合成药物并不是手性的，但那些来自天然产物的药物则几乎总是手性的（例如，青霉素类）。很显然，单一异构体药物比相应的外消旋体具有更特效的作用模式。,While in the past many drugs developed synthetically have not been chiral, those derived from natural products almost always are (for example, the penicillins). It is obvious that single-isomer drugs are more specific in mode of action compared with the corresponding racemates.,尽管如此，一个不争的事实是：进入开发的药品中大约,80,的是手性的，而现在则全为单一异构体形式；为了临床和商业利益开发单一异构体并不是其唯一的理由。,However this, together with the incentives for developing single-isomers for clinical and commercial benefits, does not solely account for the fact that around 80% of drugs entering development are chiral, exclusively now in single-isomer form.,相反，这是一个为了寻找到更大特异性的相互作用而日益增加药物结构的复杂性的结果。作为这种日益增加的复杂性的一个标志，现在的药物合成从基本有机化学品开始，通常需要大约,12,步。而大约十年前，,平均而言,，则合成步骤的数字只需要一半。,Rather this is a consequence of the increased complexity of drug structures today as greater selectivity of action is sought. As an indication of this increased complexity, a drug today will typically need around a dozen steps for its synthesis from basic organic chemicals. About ten years ago, only half this number would,on average, have been required.,手性技术已走过了很长的发展历程。本文不仅限于它在药物方面有着最显著的应用，其作用也扩展到其他领域中。它已应用于生化药剂，农药，芳香和香料化学品，染料及颜料，液晶，非线性光学材料和聚合物。事实上，手性技术显示出一个巨大的尚未得到充分实现的商业机遇。,Chiral technology has progressed a long way. This article is confined to its most visible application in pharmaceuticals, but its role extends well into other fields. It has found applications in biochemicals, pesticides, aroma and flavour chemicals, dyes and pigments, liquid crystals, non-linear optical materials, and polymers. In fact, chiral technology represents a huge commercial business opportunity that has yet to be fully realized.,A summary of available chiral technology for obtaining single-isomers is listed below. Some of these, such as fermentation and crystallisation, have long been available to chemists but their successful application required specialist expertise (for example, microbiology for the former, physical chemistry for the latter). Their use has also been patchy, as experience indicated that they could only,address,some chiral problems.,获得单一异构体的实用手性技术总结如下。其中的一些方法，如发酵和结晶，长期以来一直被化学家所采用，但它们的成功应用需要专门的技术（例如，发酵需要微生物学知识，而结晶需要物理化学知识）。但它们的作用是补缀的，因为经验表明，它们只能解决某些手性问题。,Together with newer methods, the limitations are being lifted, as the impetus to buy in the special expertise, and the will to integrate different technologies together in a single process, is motivated by the increasing value of the overall expertise in what is now an inescapable need in drug synthesis.,由于购买专门技术的推动，（这些方法）与更新的方法结合使用，其局限性消失；以及将各种技术整合在一起形成单一工艺的意愿，都是受到了日益增值的总体技术的激励，该总体技术已成为一个在药物合成中所无法回避的需求。,其中，将手性首次引入合成中总共有三个选项：,手性池，其中必要的构型由起始原料提供，并且在经过任何合成步骤后的残留物中也始终被保持；,At the point where chirality is first introduced into a synthesis there are three options:,the,chirality,pool, where the requisite configuration is provided for in the starting materials used and is maintained throughout the remainder of any synthesis;,拆分方法，其中的前体或物料提供一种消旋体混合物，必须经过分离而得到需要的异构体。在较有利的情况下，不需要的异构体可用于通过把它重新变回消旋体而再进行拆分，或将其构型转化使得也能提供需要的异构体；或,不对称合成，其中的单一异构体产品源自将不对称性直接引入非手性材料。,resolution methods, where the precursor or material is provided as a,racemic,mixture and has to be separated to give the required isomer. In,favourable,cases the undesired isomer can be used either by turning it back into,racemate,which can be resolved again or inverting its configuration so that it too provides the required isomer; or,asymmetric synthesis, where the single-isomer product is derived by introducing the asymmetry directly into a non-,chiral,material.,手性池,最简单的获得单一异构体的途径是直接天然资源中分离得到，在所有情况下，在植物、动物或微生物的自然界中所固有的手性不贵且易得，也已被使用。一个例子就是抗癌药物,紫杉醇，存在于太平洋紫杉中。紫杉醇的结构复杂性使得采用化学全合成来供应药物不切合实际。但是，合成化学可以帮助从树上得到的丰富的中间体上附上一个对紫杉醇活性起关键作用的侧链。,Chirality pool methods,The simplest access to single isomers is their direct isolation from natural sources and in all cases the inherent chirality of Nature - in plants, animals or microorganisms which are inexpensive and readily available- has been used. An example is the anticancer drug,Taxol, present in the Pacific Yew tree.,Taxol,s structural complexity makes total chemical synthesis impractical for drug supply. However, synthetic chemistry can help by attaching a side chain that is key to,Taxol,s activity onto a more abundant intermediate from the tree.,Other examples are the penicillins and Mercks cholesterol lowering agent lovastatin which are derived by microbial fermentation. In both cases synthetic chemistry has also been applied to modify the fermentation products to give better drugs,(such as amoxicillin (,阿莫西林,) and simvastatin (,辛伐他丁,), respectively, which have modified side chains),.,其他的例子，如青霉素和默克公司的降胆固醇药,洛伐他汀都是源自微生物发酵。在这两种情况下合成化学也适用于修饰发酵产品，以提供更好的药物,(,例如，阿莫西林和辛伐他丁就是分别修饰侧链而成的,),。,Apart from the production of complete drugs, Nature also makes available to the chirality pool useful building blocks like the natural amino acids or sugars.,(L-Aspartic acid (,天冬氨酸,), for example, is used by Monsanto to give the sweetener Aspartame (,阿斯巴甜,).,Nowadays, some chemically produced chiral materials are becoming commodities and they too can be considered to have entered the chirality pool -,(S)-malic acid (,苹果酸,) and the (R)- and (S)-glycidols (,缩水甘油,) are examples of this,.,除了成药的生产，自然界也能够提供像天然氨基酸或糖类的有用砌块作为手性池。,(,例如，,L-,天冬氨酸就被孟山都公司用来生产甜味剂,阿斯巴甜,),。,目前，一些化工生产的手性物质正成为商品，它们也可被认为已成为手性池,(,例如,(S)-,苹果酸，,(R)-,和,(S)-,缩水甘油,),。,Resolution methods,Racemates are easy to make and there are many ways to separate them into enantiomers. The oldest route, classical resolution, uses a chiral acid or base that forms a salt with the racemate. A great many drugs are made in this way. For instance, Syntex has developed a resolution for the (S)-enantiomer anti-inflammatory drug naproxen using an alkylglucamine resolving agent. A related method covalently binds an auxiliary like menthol or further purification of the separated diastereoisomers.,光学拆分法,外消旋体容易制备，并有很多方法可将它们分离得到其对映体。 最古老的路线,经典拆分，就是利用手性酸或碱与外消旋体生成盐。许多药物都是以这种方式生产的。例如，,Syntex,（美国先达公司）发展了一种使用烷基葡胺拆分剂，拆分得到,(s)-,对映体抗炎药,萘普生。相关的方法还需采用薄荷醇作共价键合的助剂或进一步纯化已分离得到的对映异构体。,Both of these approaches need stoichiometric amounts of another agent but resolution can be done directly by physical methods. Chromatography on a chiral stationary phase is one, especially useful for providing pre-clinical and early-clinical quantities (as well as, of course, assaying enantiomeric composition). Similar physical separations can be achieved by membrane or extraction systems where one phase contains the racemate and another a chiral selector which will selectively draw out one of the isomers.,这两种方法都需要化学计量的另一种试剂，但拆分也可直接采用物理方法来实现。色谱法中手性固定相方法就是其一，尤其适合提供有用的临床前和早期临床用的（药品）数量（当然也包括测定对映体组成）。类似的物理分离，可通过膜或提取系统来实现，其中一相含有消旋体，而另一相中含有可选择性分离出其中一个异构体的手性选择试剂。,When Drug Molecules Look in the Mirror,从镜子中看药物分子,When Drugs Molecules Look in the Mirror,从,Louis Pasteur,分离出酒石酸的对映异构体已经过了大约,150,年了。从希腊文字“,enantio,”派生出来，意为相反的，对映异构体是不可重叠的镜像结构。因为这对“双胞胎（孪晶）”除了偏振光的旋转方向不同外，拥有完全相同的物理性质，它们通常被认为是单一实体,这一点被全世界的药品监管机构所特别认可的。但对映异构体受到手性环境（即环境由一个孪晶构成，而非另外一个）的影响会表现出明显不同的化学行为。,24,数十种外消旋体药物的单个对映异构体在生物活性上的差异已经被报道。虽然治疗活性往往存在于一个孪晶中，而另一个可能会导致不期望的副作用。沙利度胺（反应停）惨剧就是一个令人警示的例子。在二十世纪六十年代里，许多服用外消旋体的沙利度胺的孕妇产下了畸形婴儿。随后的调查显示只有该药品的右旋体会对老鼠的胚胎造成同样的生育缺陷。如果这一镇静剂是以,L-,沙利度胺（即偏振光逆时针旋转的单一对映异构体）的形式予以服药（或给药）的话，那场灾难也许将从不会发生。,26,27,Thank you,汇报结束,谢谢大家,!,请各位批评指正,