1.4天然橡胶橡胶一一用于个不平常化合物的一个与众不同的名字一是一个天然存在于400多种不同植物中的烯烃聚化合物。当然，主要来源是橡胶树（Hevea brasiliensis），其树皮上的一薄切片滴下来的物质就是粗产品。作为氧元素的发现者和最早的橡胶化学的研究者，JosephPriestley给出了橡胶这个名字，一个简单的原因就是橡胶最开始被用于擦掉纸上的铅笔标记苟聚乙烯和其它简单的烯烃聚合物不同，天然橡胶是共轭二烯异戊二烯或2-甲基-1,3.丁二烯的聚合物。通过异戊二烯单体的1,4加成发生了聚合作用，从而生成了每隔4个碳原子就含有碳碳双键的聚合物（见4.1节）。如下面结构所示，这些双键是Z型结构。被称作乳胶的粗橡胶，可以从树上收集。该乳胶分散在水中，洗提，干燥并在空气中加热凝结，而形成了含有5000多个单体的聚合物，分子量是200000一500000之间。这个粗凝结物太软和太粘而不能使用，直到在硫元素中加热才能变硬，这个过程称作“硫化”根据至今仍然不能很好理解的这个机理，因硫化形成的碳硫健使橡胶交叉键链在一起，使聚合物变得更坚硬和粘稠。变硬的程度不同，也就会产生足够软的用于机动车轮胎的橡胶和足够硬的保龄球（硬橡胶）。橡胶显著的性能是能拉长，并能压缩到原来的形状，这是因为双键造成了聚合物链形状的改变。这些双键能使聚合物弯曲和纽结，并因此而阻止相邻链从单体紧紧压缩成半结晶状态。当伸长时，随意卷曲的链会伸直，并且朝向拉长的方向，但由于交叉联结而不会拉断。当不拉开时，聚合物就会恢复到原来随意的状态
11 1．4 天然橡胶 橡胶――用于一个不平常化合物的一个与众不同的名字――是一个天然存在于 400 多种不同植物中的烯烃聚化合物。当然，主要来源是橡胶树（Hevea brasiliensis），其树皮 上的一薄切片滴下来的物质就是粗产品。作为氧元素的发现者和最早的橡胶化学的研究 者，Joseph Priestley 给出了橡胶这个名字，一个简单的原因就是橡胶最开始被用于擦掉纸 上的铅笔标记。 与聚乙烯和其它简单的烯烃聚合物不同，天然橡胶是共轭二烯异戊二烯或 2-甲基-1,3- 丁二烯的聚合物。通过异戊二烯单体的 1,4 加成发生了聚合作用，从而生成了每隔 4 个碳 原子就含有碳碳双键的聚合物（见 4.1 节）。如下面结构所示，这些双键是 Z 型结构。 被称作乳胶的粗橡胶，可以从树上收集。该乳胶分散在水中，洗提，干燥并在空气中 加热凝结，而形成了含有 5000 多个单体的聚合物，分子量是 200000－500000 之间。这个 粗凝结物太软和太粘而不能使用，直到在硫元素中加热才能变硬，这个过程称作“硫化”、 根据至今仍然不能很好理解的这个机理，因硫化形成的碳硫健使橡胶交叉键链在一起，并 使聚合物变得更坚硬和粘稠。变硬的程度不同，也就会产生足够软的用于机动车轮胎的橡 胶和足够硬的保龄球（硬橡胶）。 橡胶显著的性能是能拉长，并能压缩到原来的形状，这是因为双键造成了聚合物链 形状的改变。这些双键能使聚合物弯曲和纽结，并因此而阻止相邻链从单体紧紧压缩成半 结晶状态。当伸长时，随意卷曲的链会伸直，并且朝向拉长的方向，但由于交叉联结而不 会拉断。当不拉开时，聚合物就会恢复到原来随意的状态
5AspirinNSAIDSand Cox-2 InhibitorWhateverthe causetennis elbow,sprainedanklea wrenched kneepairand inflammation seem to go together.Theynoweintheoowertulgescortisonepotent-inflaminflammatiorropemsarofteneaicommover-thedicationcalledanNSAID,ornonsteroidal anti-infdriThemost common NSAID is aaspirin , or acetylsalicylic acid, whaektothe1800s1O0BCthathahacalleoonveriedbvreactiongive salicylic acidSalicylic acid is even moreeffective than salicinforreducingoxidizedtofevers and alsohas bothanasicand anti-inflammatorypropertiesUnfortunately,salicylicacidcorrosiveto the walls of the stomach for evervday use.Conversion of the pheo0nol-OHoracetvlsalicvlic acid.which proved just as ssalicvicaclesscorrosivetoCH,OHCOOHCOOHOHOFOCCHaSalicyl alcoholSalicylic acidOAcetyacid(Aspirin)Although extraordinary in its powers, aspirin is also more dangerous than commonlybelieved..onlyt 15ocanhfatal to a small child , and aspirihblaadand allergicsin long-term.Evenmore serious is a condition called Reye'ssyndrome,apotentiallyfatalreaction to aspirin sometimes seen in children recoveringfrom theflu.Asaresultoftheseproblems,numerousotherNSAIDs have beendeveloped inthelasttwodecades,most notably ibuprofenand naproxenboth ibuprofen and naproxen are relatively simple aromatic compoundkeasnide-chainic acid groupibuprofen sold under the names Advil, MotrinNuprin, and others , has roughly the same potency as aspirin but is less prone to cause stomachupset. Naproxen, sold under the names Naprosyn and Aleve, also has about the same potency asaspirinbitremainsactiveinthebodysixtimeslonger
12 1．5 Aspirin, NSAIDs, and COX-2 Inhibitors Whatever the cause –tennis elbow , a sprained ankle , or a wrenched knee – pain and inflammation seem to go together. They are , however, different in their origin ,and powerful drugs are available for treating each separately . Codeine , for example , is a powerful analgesic, or pain reliever, while cortisone and related steroids are potent anti-inflammatory agents often used for treating arthritis . For minor pains and inflammation, though, both problems are often treated using a common , over-the-counter medication called an NSAID, or nonsteroidal anti-inflammatory drug. The most common NSAID is aspirin , or acetylsalicylic acid , whose use dates back to the late 1800s. It has been known since before 400 BC that fevers can be lowered by chewing the bark of willow trees. The active agent in willow bark was found in 1827 to be an aromatic compound called salicin, which could be converted by reaction with water into salicyl alcohol and then oxidized to give salicylic acid . Salicylic acid is even more effective than salicin for reducing fevers and also has both analgesic and anti-inflammatory properties . Unfortunately, salicylic acid is too corrosive to the walls of the stomach for everyday use. Conversion of the phenol-OH group into an ester, however, yield acetylsalicylic acid , which proved just as potent as salicylic acid but less corrosive to the stomach. Although extraordinary in its powers, aspirin is also more dangerous than commonly believed . only about 15g can be fatal to a small child , and aspirin can cause stomach bleeding and allergic reactions in long-term users. Even more serious is a condition called Reye’s syndrome, a potentially fatal reaction to aspirin sometimes seen in children recovering from the flu. As a result of these problems, numerous other NSAIDs have been developed in the last two decades , most notably ibuprofen and naproxen. Like aspirin , both ibuprofen and naproxen are relatively simple aromatic compounds containing a side-chain carboxylic acid group . ibuprofen, sold under the names Advil, Motrin, Nuprin, and others , has roughly the same potency as aspirin but is less prone to cause stomach upset. Naproxen, sold under the names Naprosyn and Aleve, also has about the same potency as aspirin bit remains active in the body six times longer
CH3CH3CHCOOHCHCOOHCHCH,CHCHCH.ONaprox(Advil,MoAspirinaher NSAIDs function by blocking the cyclooxygenase(COX) enzymes thatcarry out the body's synthesis of a group of substance called prostaglandins. There are two formsof the enzyme:cOx-1,which carries out the normal physiological production of prostaglandinsandCOx-2,whichmediates thebody's response to arthritis and other inflammatory conditionsUnfortunately, both Cox-1 and cOx-2 enzymes are blocked by aspirin, ibbuprofen.and otherNSAIDs.onlytheresponsetoinflamiputalsovariousprotectivetingdoylonhfunctions, including thecontrol mechanism for production ofacid in the stomachRecently, medicinal chemists have devised a number of drug that act as selectiveinhibitors of the COX-2 enzyme.Inflammation is thereby controlled without harmful side effectsCelecoxilhintroed by Monsanto under the name Celebirofecoxib,introducedbyMerchhave revolutionized the medicine treatmearthritis and otherinflammconditoCHNHF3CCHxi(Celebrex)
13 Aspirin and other NSAIDs function by blocking the cyclooxygenase(COX) enzymes that carry out the body’s synthesis of a group of substance called prostaglandins. There are two forms of the enzyme: COX-1 , which carries out the normal physiological production of prostaglandins, and COX-2, which mediates the body’s response to arthritis and other inflammatory conditions. Unfortunately, both Cox-1 and COX-2 enzymes are blocked by aspirin, ibuprofen, and other NSAIDs, thereby shutting down not only the response to inflammation but also various protective functions, including the control mechanism for production of acid in the stomach. Recently, medicinal chemists have devised a number of drug that act as selective inhibitors of the COX-2 enzyme . Inflammation is thereby controlled without harmful side effects. Celecoxib, introduced by Monsanto under the name Celebrex, and rofecoxib, introduced by Merck under the name Vioxx, have revolutionized the medicine treatment of arthritis and other inflammatory conditions
1.5阿司匹林，NSAIDS，和COX-2抑制剂疼痛和炎症总是一起发生的，而不管是什么原因造成的被网球打到的肘，扭伤的脚踝或受伤的膝盖。当然，起因不同，但在分别治疗时要使用有疗效的药物。例如，可待因是有效的止痛剂，而可的松和相关的类固醇是有效的抗炎药物，常常用来治疗关节炎。可以用被称作NSAID的药物或不含类固醇的抗炎药物来治疗小的疼痛和炎症最常用的NSAID是阿司匹林，或乙酰水杨酸，这些药物的使用可以追溯到1800年代的晚期。在公元400年就知道，嚼柳树皮可以减轻发烧。在1827年发现柳树皮的有效成分是一个称作水杨苷的芳香化合物，该化合物与水反应能转化成水杨醇，并进一步氧化成水杨酸。水杨酸比水杨苷更能有效减少发烧，并且都具有止痛和抗炎作用。不幸的是，水杨酸对胃壁有腐蚀作用而不能使用于日常生活中。当然，把苯酚中的羟基转换成酯，生成了乙酰水杨酸，已证实乙酰水杨酸具有与水杨酸一样的作用，并且对胃的腐蚀作用很小，尽管阿司匹林有很好的药效作用，但它比我们常认为的危险性要大。只有 15克的量能使一个小孩致死，也能使胃出血，长期使用也会有过敏反应。更严重的是一个称作“Reye's综合症”的条件，有时候在小孩感冒恢复过程中出现的与阿司匹林反应的致命危险。由于这些原因，在最近20年中已经开发出许多其它的NSAIDS，最显著的有异丁苯丙酸和甲氧萘丙酸。阿司匹林-店异丁苯丙酸和甲氧萘丙酸是简单的芳香化合物，并在支链上含有羧基官能团。异丁苯丙酸，也以Advil,Motrin,Nuprin 和其它的名字出售，和阿司匹林有一样的药效，但不会使胃不适。甲氧萘丙酸，也以Naprosyn和Aleve等名字出售，也与阿司匹林有相同的药效，但能在身体中保持6倍以上的活性阿司匹林和其它NSAIDS是通过妨碍环氧酶（COX）来起作用的，该酶是用来执行且称作为前列腺素的物质的合成。身体口有两种形式的酶：COX-1和COX-2。COX-用来执行前列腺素的正常生理作用，COX-2是用来调节身体对关节炎和其它炎症的反应不幸的是，阿司匹林，异丁苯丙酸和其它NSAIDS 都能阻断这两种酶，因此，不仅会关闭炎症的反应，还会关闭各种有保护作用的功能，包括在胃中胃酸产生的控制机理。最近，药物化学家开发出许多对COX-2酶选择性抑制的药物。因而能控制炎症，而没有副作用。由孟山都引进的Celb（或称作Celebrex）和Merck 公司引进的rofecoxib(或称作Vioxx)，可以用来治疗关节炎和其它的炎症
14 1．5 阿司匹林，NSAIDS, 和 COX-2 抑制剂 疼痛和炎症总是一起发生的，而不管是什么原因造成的——被网球打到的肘，扭伤的 脚踝或受伤的膝盖。当然，起因不同，但在分别治疗时要使用有疗效的药物。例如，可待 因是有效的止痛剂，而可的松和相关的类固醇是有效的抗炎药物，常常用来治疗关节炎。 可以用被称作 NSAID 的药物或不含类固醇的抗炎药物来治疗小的疼痛和炎症。 最常用的 NSAID 是阿司匹林，或乙酰水杨酸，这些药物的使用可以追溯到 1800 年代 的晚期。在公元 400 年就知道，嚼柳树皮可以减轻发烧。在 1827 年发现柳树皮的有效成 分是一个称作水杨苷的芳香化合物，该化合物与水反应能转化成水杨醇，并进一步氧化成 水杨酸。水杨酸比水杨苷更能有效减少发烧，并且都具有止痛和抗炎作用。不幸的是，水 杨酸对胃壁有腐蚀作用而不能使用于日常生活中。当然，把苯酚中的羟基转换成酯，生成 了乙酰水杨酸，已证实乙酰水杨酸具有与水杨酸一样的作用，并且对胃的腐蚀作用很小。 尽管阿司匹林有很好的药效作用，但它比我们常认为的危险性要大。只有 15 克的量 能使一个小孩致死，也能使胃出血，长期使用也会有过敏反应。更严重的是一个称作 “Reye’s 综合症”的条件，有时候在小孩感冒恢复过程中出现的与阿司匹林反应的致命危 险。由于这些原因，在最近 20 年中已经开发出许多其它的 NSAIDS，最显著的有异丁苯 丙酸和甲氧萘丙酸。 与阿司匹林一样，异丁苯丙酸和甲氧萘丙酸是简单的芳香化合物，并在支链上含有 羧基官能团。异丁苯丙酸，也以 Advil,Motrin,Nuprin 和其它的名字出售，和阿司匹林有一 样的药效，但不会使胃不适。甲氧萘丙酸，也以 Naprosyn 和 Aleve 等名字出售，也与阿 司匹林有相同的药效，但能在身体中保持 6 倍以上的活性。 阿司匹林和其它 NSAIDS 是通过妨碍环氧酶（COX）来起作用的，该酶是用来执行 身体中一组称作为前列腺素的物质的合成。有两种形式的酶：COX-1 和 COX-2。COX-1 用来执行前列腺素的正常生理作用，COX-2 是用来调节身体对关节炎和其它炎症的反应。 不幸的是，阿司匹林，异丁苯丙酸和其它 NSAIDS 都能阻断这两种酶，因此，不仅会关 闭炎症的反应，还会关闭各种有保护作用的功能，包括在胃中胃酸产生的控制机理。 最近，药物化学家开发出许多对 COX-2 酶选择性抑制的药物。因而能控制炎症，而 没有副作用。由孟山都引进的 Celecoxib（或称作 Celebrex）和 Merck 公司引进的 rofecoxib(或称作 Vioxx)，可以用来治疗关节炎和其它的炎症
1.6Chiralityin Naturejust as different stereoisomeric forms as a chiral molecule have different physicalproperties, they usually have different biological properties as . For example, the (+)enantiomerof limonene has the odor of oranges, but the () enantiomerhastheodoroflemonsJ美8+).Lim(inlemonspeMore dramatic exampleof how a change in chirality can affect the biological properties of amoleculearefound inmany drugs,such asfluoxetine,a heavily prescribed medication sold underthe trade name Prozac. Racemic fluoxetine is an extraordinarily effective antidepressant. but it hasemarkablewell inergoing clinical evaluationnterlude"Chiral Drugsorevthe endof thischaptergivesother exampleHH(S)-FluoxetinaineWhydodifferent stereoisomershavedifferent biologicalproperties?Toexertitsbiologicalaction, a chiral molecule must fit into a chiral receptor at a target site, much as a hand fits into aglove. But just as a right hand can fit only into a right-hand glove, so a particular stereoisomer calitonlvintrhavingthecomplementary shape.Any other serwillbeODmisfit, like a right hand in a left-handed glove. A schentation ofthbetween a chiral moleculeand a chiral biological receptor is shown in Figure 6.15.Onenantiomerfits the receptor perfectly,but the other does not
15 1．6 Chirality in Nature just as different stereoisomeric forms as a chiral molecule have different physical properties, they usually have different biological properties as . For example, the (+)enantiomer of limonene has the odor of oranges, but the (-) enantiomer has the odor of lemons More dramatic example of how a change in chirality can affect the biological properties of a molecule are found in many drugs, such as fluoxetine, a heavily prescribed medication sold under the trade name Prozac. Racemic fluoxetine is an extraordinarily effective antidepressant, but it has no activity against migraine. The pure S enantiomer, however, works remarkable well in preventing migraine and is now undergoing clinical evaluation. The Interlude “Chiral Drugs” at the end of this chapter gives other example. Why do different stereoisomers have different biological properties? To exert its biological action, a chiral molecule must fit into a chiral receptor at a target site, much as a hand fits into a glove. But just as a right hand can fit only into a right-hand glove, so a particular stereoisomer can fit only into a receptor having the proper complementary shape . Any other stereoisomer will be a misfit, like a right hand in a left-handed glove. A schematic representation of the interaction between a chiral molecule and a chiral biological receptor is shown in Figure 6.15. One enantiomer fits the receptor perfectly, but the other does not