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1、The professional English of pharmaceutical engineeringWang XinliangEast China University of Science and Technology 概 念 簡(jiǎn) 介手性藥物: 具有手性結(jié)構(gòu)及藥理活性的具有治療疾病作用的手性化合物。藥理作用：通過其余體內(nèi)大分子進(jìn)行手性識(shí)別和匹配產(chǎn)生活性而起到治療的作用。一對(duì)對(duì)映體的手性藥物在手性結(jié)構(gòu)上的差異往往會(huì)導(dǎo)致它們?cè)谒幚砘钚?、藥物代謝及毒性等方面產(chǎn)生不同的體內(nèi)的藥理活性。v根據(jù)一對(duì)對(duì)映體的手性藥物藥理作用和藥效，可分為： 一個(gè)有藥理活性，而它的對(duì)映體沒有藥理活性； 一對(duì)對(duì)映體有
2、相反的藥理活性，一個(gè)有活性，對(duì)映體甚至可能顯毒性； 一對(duì)對(duì)映體藥理活性相同，但有差別； 一對(duì)對(duì)映體有迥乎不同的藥理活性； 一對(duì)對(duì)映體藥理活性完全相同。 2 Wordsencompasschirality (a. chiral)enantiomerdiastereomermesomerracemateunwantedclear-cuttolerabilityimpetusbuilding blockcholesterolmentholstationary/mobile phase assaychiral selectortartaric acidensuingembryoscountercloc
3、kwise vt. 包含；包圍，環(huán)繞n. 手(征)性 (a. 手(征)性的)n. 對(duì)映(異構(gòu))體n.非對(duì)映(異構(gòu))體n. 內(nèi)消旋體n. 外消旋體(化合物)a. 有害的；不需要的a.清晰的；輪廓鮮明的n.耐受性; 容忍度n. 動(dòng)力；促進(jìn)；沖力n. 砌塊；積木；構(gòu)件n.膽固醇；膽甾醇n. 薄荷醇，薄荷腦固定相/流動(dòng)相n.化驗(yàn)，試驗(yàn)；vt. 分析，測(cè)試手性選擇試劑酒石酸a. 跟著發(fā)生的 n. 胚胎；晶胎adv. 逆時(shí)針地 手性幾乎并不是化學(xué)中的新概念，但在過去的幾年里手性技術(shù)的進(jìn)步已對(duì)制藥研究和開發(fā)產(chǎn)生了越來越大的影響。如今，手性技術(shù)對(duì)合理的藥物設(shè)計(jì)正起著強(qiáng)大的影響。 Chirality is ha
4、rdly 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. 尤其在尋求高選擇性作用（機(jī)制）時(shí)，手性技術(shù)有助于新受體為基礎(chǔ)的或酶抑制的小分子藥物的構(gòu)思（概念的形成）和發(fā)現(xiàn)。手性技術(shù)被人們所認(rèn)可主
5、要是因?yàn)楝F(xiàn)在已有大量可用于制造單一對(duì)映體手性藥物的技術(shù)。 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-e
6、nantiomer chiral drugs. 對(duì)那些不熟悉手性技術(shù)的人們而言，該術(shù)語包括生產(chǎn)單一手性形式(對(duì)映體)化合物的技術(shù)，具有足夠復(fù)雜性的分子結(jié)構(gòu)的化合物是手性的；也就是說，這時(shí)分子不能與其鏡像疊加(重合)。隨著分子變得更加復(fù)雜，藥品的特異作用性增加；對(duì)更具特異性作用的藥品的追求將導(dǎo)致更大比例的藥品為手性。 For those unfamiliar with chiral technology, the term encompasses the range of techniques for producing the single-handed forms (enantiomers)
7、 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
8、. 如果某一藥物是手性的，在生物學(xué)范疇里其對(duì)映體總具有不同的活性。一種藥物可能會(huì)與細(xì)胞受體發(fā)生特異性的相互作用而產(chǎn)生期望的結(jié)果，而另外一種藥物則可能產(chǎn)生無用的作用，或通過某些其他的相互作用而可能導(dǎo)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 mig
9、ht have no useful application or might have an unwanted effect through some other interaction. 在明確的例子中，手性化合物的一個(gè)異構(gòu)體是“對(duì)人體有益的”，而另一個(gè)異構(gòu)體則是“對(duì)人體有害的”，發(fā)展單一異構(gòu)體的藥物以加強(qiáng)其安全性和耐受性，可以獲得顯而易見的利潤。此外，這也可以通過監(jiān)管渠道加快藥品的發(fā)展，從而節(jié)省研發(fā)成本。 In the clear-cut example where one isomer of a chiral compound is good and the other bad, the
10、re 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 u拆分方法，其中的前體或物料提供一種消旋體混合物，必須經(jīng)過分離而得到需要的異構(gòu)體。在較有利的情況下，不需要的異構(gòu)體可用于通過把它重新變回消旋體而再進(jìn)行拆分，或?qū)⑵錁?gòu)型轉(zhuǎn)化使得也
11、能提供需要的異構(gòu)體；或 u不對(duì)稱合成，其中的單一異構(gòu)體產(chǎn)品源自將不對(duì)稱性直接引入非手性材料。u 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
12、 again or inverting its configuration so that it too provides the required isomer; oru asymmetric synthesis, where the single-isomer product is derived by introducing the asymmetry directly into a non-chiral material. 手性池 最簡(jiǎn)單的獲得單一異構(gòu)體的途徑是直接天然資源中分離得到，在所有情況下，在植物、動(dòng)物或微生物的自然界中所固有的手性不貴且易得，也已被使用。一個(gè)例子就是抗癌藥物紫
13、杉醇，存在于太平洋紫杉中。紫杉醇的結(jié)構(gòu)復(fù)雜性使得采用化學(xué)全合成來供應(yīng)藥物不切合實(shí)際。但是，合成化學(xué)可以幫助從樹上得到的豐富的中間體上附上一個(gè)對(duì)紫杉醇活性起關(guān)鍵作用的側(cè)鏈。 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 inexpen
14、sive and readily available- has been used. An example is the anticancer drug Taxol, present in the Pacific Yew tree. Taxols structural complexity makes total chemical synthesis impractical for drug supply. However, synthetic chemistry can help by attaching a side chain that is key to Taxols activity
15、 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
16、 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膽固醇藥洛伐他汀都是源自微生物發(fā)酵。在這兩種情況下合成化學(xué)也適用于修飾發(fā)酵產(chǎn)品，以提供更好的藥物(例如，阿莫西林和辛伐他丁就是分別修飾側(cè)鏈而成的)。 Apart from the production of complete drugs, Nature also makes available to the chirality pool useful building block
17、s 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
18、(蘋果酸) and the (R)- and (S)-glycidols (縮水甘油) are examples of this. 除了成藥的生產(chǎn)，自然界也能夠提供像天然氨基酸或糖類的有用砌塊作為手性池。 (例如，L-天冬氨酸就被孟山都公司用來生產(chǎn)甜味劑阿斯巴甜) 。目前，一些化工生產(chǎn)的手性物質(zhì)正成為商品，它們也可被認(rèn)為已成為手性池(例如(S)-蘋果酸，(R)- 和 (S)-縮水甘油)。 Resolution methods Racemates are easy to make and there are many ways to separate them into enantiomers.
19、 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
20、method covalently binds an auxiliary like menthol or further purification of the separated diastereoisomers.光 學(xué) 拆 分 法 外消旋體容易制備，并有很多方法可將它們分離得到其對(duì)映體。 最古老的路線經(jīng)典拆分，就是利用手性酸或堿與外消旋體生成鹽。許多藥物都是以這種方式生產(chǎn)的。例如，Syntex（美國先達(dá)公司）發(fā)展了一種使用烷基葡胺拆分劑，拆分得到(s)-對(duì)映體抗炎藥萘普生。相關(guān)的方法還需采用薄荷醇作共價(jià)鍵合的助 劑或進(jìn)一步純化已分離得到的對(duì)映異構(gòu)體。 Both of these appro
21、aches 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). Simil
22、ar 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. 這兩種方法都需要化學(xué)計(jì)量的另一種試劑，但拆分也可直接采用物理方法來實(shí)現(xiàn)。色譜法中手性固定相方法就是其一，尤其適合提供有用的臨床前和早期臨床用的（藥品）數(shù)量（當(dāng)然也包括測(cè)定對(duì)映體組成）。類似的物理分離，可通過膜或提
23、取系統(tǒng)來實(shí)現(xiàn)，其中一相含有消旋體，而另一相中含有可選擇性分離出其中一個(gè)異構(gòu)體的手性選擇試劑。 v When Drug Molecules Look in the Mirror從鏡子中看藥物分子 When Drugs Molecules Look in the Mirror 從Louis Pasteur分離出酒石酸的對(duì)映異構(gòu)體已經(jīng)過了大約150年了。從希臘文字“enantio”派生出來，意為相反的，對(duì)映異構(gòu)體是不可重疊的鏡像結(jié)構(gòu)。因?yàn)檫@對(duì)“雙胞胎（孿晶）”除了偏振光的旋轉(zhuǎn)方向不同外，擁有完全相同的物理性質(zhì)，它們通常被認(rèn)為是單一實(shí)體這一點(diǎn)被全世界的藥品監(jiān)管機(jī)構(gòu)所特別認(rèn)可的。但對(duì)映異構(gòu)體受到手性環(huán)境（即環(huán)境由一個(gè)孿晶構(gòu)成，而非另外一個(gè)）的影響會(huì)表現(xiàn)出明顯不同的化學(xué)行為。 24 數(shù)十種外消旋體藥物的單個(gè)對(duì)映異構(gòu)體在生物活性上的差異已經(jīng)被報(bào)道。雖然治療活性往往存在于一個(gè)孿晶中，而另一個(gè)可能會(huì)導(dǎo)致不期望的副作用。沙利度胺（反應(yīng)停）慘劇就是一個(gè)令人警示的例子。在二十世紀(jì)六十年代里，許多服用外消旋體的沙利度胺的孕婦產(chǎn)下了畸形嬰兒。隨后的調(diào)查顯示只有該藥品的右旋體會(huì)對(duì)老鼠的胚胎造成同樣的生育缺陷。如果這一鎮(zhèn)靜劑是以L-沙利度胺（即偏振光逆時(shí)針旋轉(zhuǎn)的單一對(duì)映異構(gòu)體）的形式予以服藥（或給藥）的話，那場(chǎng)災(zāi)難也許將從不會(huì)發(fā)生。 26 27
制藥工程 專業(yè)英語 Unit 21
