绿色化学第三章

1、Chapter 3,Designing Safer Chemicals,General Principles for Designing Safer Chemicals,Methods for Designing Safer Chemicals,Chapter 3 Designing Safer Chemicals,3.1 General Principles for Designing Safer Chemicals,Two main ways to avoid Hazard and Toxicity 1：make it not possible to enter the body, 2：m

2、ake it not possible to affect the bio-chemical and physiological processes(生物化学和生理过程) hazardously. to human beings, to environment Direct hazard Metabolism; Presence of other substituents that may attenuate the reactivity of the electrophilic substituent.,2：Designing Safer Electrophilic Substances,I

3、deally, electrophilic substituents should never be incorporated into a substance. However the electrophilic group is often necessary for the intended commercial use of the substance. This poses a dilemma for the chemist who wishes to design an electrophile to react with a nucleophile necessary for i

4、ntended commercial use but not with biological nucleophiles in individuals exposed to the substance. As impossible as this may seem, there are approaches that chemists can use to design safer, commercially-useful electrophilic substances.,2：Designing Safer Electrophilic Substances,（1）Decreasing the

5、electrophilicity of the molecules,Avoiding the interaction of the molecule with the cellular macromolecule in the tissues, thus reducing the toxicity,Example,Incorporation of a methyl (-CH3) group onto the -carbon (to provide a methacrylate) decreases the electrophilicity (i.e., reactivity) of the -

6、carbon and, hence, methacrylates (甲基丙烯酸酯) do not undergo 1,4-Michael addition reactions as readily. Methacrylates often have commercial efficacy similar to acrylates in many applications, but are less likely to cause cancer because they are less reactive.,Acrylates(丙烯酸酯), for example, contain an ,-u

7、nsaturated carbonyl system,Acrylates(丙烯酸酯),CH2=CHCOOCH2CH3,Carcinogenic (致癌),Methacrylates (甲基丙烯酸酯),CH2=C（CH3）COOCH3,Non-carcinogenic,Example,This point can be demonstrated by comparing ethyl acrylate, which causes cancer in experimental animals, to methyl methacrylate, which does not cause cancer i

8、n a similar assay. It seems logical that placement of a methyl group onto the -carbon of similar , -unsaturated systems may also decrease toxicity without sacrificing commercial utility.,（2） electrophilic-masking approach,Reactants for the production of the product,Masking agents,Removing the maskin

9、g agent,The product is regenerated in situ for use,in the production, transportation, and storage,The hazardousness is eliminated,3：Toxic Mechanisms Involving Bioactivation to Electrophiles and the design of related molecule.,The majority of biochemical reactions that lead to formation of electrophi

10、lic metabolites involve cytochrome(细胞色素)P450-catalyzed oxidations . In these reactions a particular portion of the molecule is bioactivated to become an electrophile.,Examples,4-Alkyl-Phenol(4-烷基酚) Allyl Alcohols(烯醇) Propargl Archohols(炔丙基醇) Alkens(烯烃) and Alkynes(炔烃),3.2 Designing Safer Chemicals U

11、sing Structure-Activity (Toxicity) Relationships,As discussed earlier, substances that are capable of producing a biological effect (pharmacological or toxicological) contain a structural feature that bestows the intrinsic biological property.,Qualitative Structure-Activity Relationships,Quantitativ

12、e Structure-Activity Relationships (QSARs),pharmacophore / toxicophore,In the case of drugs, in which the biological response is desired, this structural feature is referred to genetically as the pharmacophore. In the case of commercial chemical substances, in which the biological effect is undesire

13、d (toxic), the structural feature is referred to genetically as the toxicophore. In either case, the structural feature elicits(引起) its biological effect through interaction with a specific biomolecular site of action to cause changes in cellular biochemistry.,Substances that contain the same pharma

14、cophore or toxicophore are therefore likely to exhibit the same pharmacological or toxicological properties.,The relative potency(力量) amongst the substances in their ability to cause the biological effect may vary substantially. The relative potency is directly related to the specific or incremental

15、(增量的) structural differences between the substances and the influence these differences have on the ability of the toxicophore (or pharmacophore) to interact with its biomolecular site of action.,General Principle,Definition: The ability of substances belonging to the same chemical class to a cause

16、a particular biological effect and the influence that their structural differences have on potency are referred to as structure-activity relationships (SARS).,General Principle,The relationship between structure and activity for a given group of substances becomes much clearer when the mechanism of

17、biological action is known. Structure-activity relationships are useful for several reasons.,General Principle,First, a series of structurally-similar chemicals with a measured pharmacological or toxicological response may allow one to infer similar pharmacological or toxic effects for ananalogous u

18、ntested substance.,General Principle,Second, structure-activity relationships can be used to design new, analogous substances such that the biological activity is either maximized (in the case of drug substances) or minimized (in the case of commercial chemical substances).,General Principle,History

19、: Structure-activity relationships have been used for decades by medicinal chemists in the design of highly efficacious drug substances, by the U.S. Environmental Protection Agency for assessing the toxicity of new, untested commercial chemicals prior to commercialization.,General Principle,Despite

20、the structure-activity data available for many classes of commercial chemical substances, however, the use of structure-activity relationships has been given little attention by chemists as a rational approach for designing new, less toxic commercial chemical substances.,3.2.1 Qualitative Structure-

21、Activity Relationships,With qualitative structure-activity relationships, the correlation of toxic effect with structure is made by visual comparison of the structures of the substances in the series and the corresponding effects on the toxicity. From qualitative examination of structure-activity da

22、ta the chemist may be able to see a relationship between structure and toxicity, and identify the least toxic members of the class as possible commercial alternatives to the more toxic members.,Qualitative Structure-Activity Relationships,In addition the chemist may infer from the relationship the s

23、tructural characteristics that reduce toxic potency, thereby providing a rational basis to design new, less toxic analogous substances.,Qualitative Structure-Activity Relationships,The larger the data set the more apparent the relationship between structure and activity becomes, but small data sets

24、can nonetheless be quite useful. The application of qualitative structure-activity relationships for the design of safer chemicals is demonstrated below using several classes of important commercial chemical substances.,Examples of Designing Safer Chemicals using Qualitative SARS,Polyethoxylated Non

25、ylphenols (聚乙氧基壬酚) Glycidyl Ethers（缩水甘油醚） 1，2，4-Triazole-3-thione （ 1，2，4-三唑-3-硫酮） Carboxylic Acids （羧酸）,Polyethoxylated Nonylphenols(聚乙氧基壬酚) used as emulsifiers/surfactants, predominately in detergents and inks,C9H19C6H4O(CH2CH2O)nCH2CH2OH,n=1429, intense myocardial (心肌的) necrosis(坏疽) n14 or n29， n

26、o such effects,It has been observed that these substances cause an intense myocardial (心肌的) necrosis(坏疽) in dogs and guinea(几内亚) pigs within 5 days when administered orally at a dose of 40 mg/kg/day when the extent of ethyoxylation ranges between 14 to 29 ethoxy units,Polyethoxylated Nonylphenols us

27、ed as emulsifiers/surfactants, predominately in detergents and inks,Although the mechanism of myocardial toxicity is unknown, the structure-activity relationship data described above are nonetheless useful in designing safer polyethoxylated nonylphenols. Clearly, chemists should intentionally design

28、 and use polyethoxylated nonylphenols with fewer than 14 or more than 29 ethoxy subunits.,Glycidyl Ethers (缩水甘油醚) having the type of structure below,used as synthetic reagents for a variety of purposes,Glycidyl Ethers (缩水甘油醚),It has been shown that glycidyl ethers of the type represented above are m

29、utagenic(诱导有机体突变的) and cause testicular(双丸状的) lesions(损害) in rats and rabbits following oral and inhalation administration when the alkyl substituent is an n-octyl (n = 7), n-nonyl (n=8) or n-decyl (n=9) . These toxic effects are not observed, however, when the alkyl substituent ranges from dodecyl

30、(n=11) to tetradecyl (n=13).,n=79， mutagenic, testicular lesions(引发睾丸损伤) n=1113, no such toxicity,Glycidyl Ethers (缩水甘油醚),As in the case of polyethoxylated nonylphenols, the mechanism responsible for the toxicity of these glycidyl ethers is not known, although the epoxide moiety is almost certainly

31、the toxicophore. Nonetheless, these structure-activity relationship data are useful for the design of safer glycidyl ethers. Chemists should avoid designing and using glycidyl ethers of the type represented above in which the length of the alkyl moiety ranges from 8 to 10 carbons. Whenever possible,

32、 chemists should design and use glycidyl ethers in which the length of the alkyl moiety is at least 12 carbon atoms.,l,2,4-Triazole-3-thiones(1，2，4-三唑-3-硫酮),The thiocarboxamide (-C-N) group is found in a variety of commercial substances. However, the thiocarboxamide group is often toxicophoric. Many

33、 thiocarboxamides are toxic to the thyroidgland (甲状腺) (i.e., thyrotoxic(甲状腺机能亢进的).,l,2,4-Triazole-3-thiones(1，2，4-三唑-3-硫酮),The thyrotoxicity is manifested by an inhibition in the thyroids ability to synthesize thyroid hormone(甲状腺激素), which ultimately leads to hypothyroidism(甲状腺机能衰退). In fact, some t

34、hiocarboxamides (乙二酰二胺)(e.g., propylthiouracil(丙基硫尿嘧啶), methimazole(甲硫咪唑) are used medically to treat hyperthyroidism (甲亢).,l,2,4-Triazole-3-thiones(1，2，4-三唑-3-硫酮),The specific mechanism by which the thiocarboxamide moiety is thyrotoxic is unknown, but is believed to involve inhibition of thyroid pe

35、roxidase, the enzyme that catalyzes the incorporation of iodine into tyrosine (酪氨酸) residues during thyroid hormone synthesis.,The structure and toxicity of substituted l,2,4-Triazole-3-thiones,General R1 R2 R3 Relative Toxicity Structure CH3 H H 1.0 H CH3 H 1.2 H H CH3 212.0 CH3 H CH3 7.1 H H C6H5

36、5.7 CH3 CH3 H 4.7 H H H 3.6,Carboxylic Acids,（C）CCCCO2H,n 4 3 2,The toxicity of carboxylic acids includes hepatotoxicities(肝中毒), Fetus deforming(畸胎作用), etc. It is rather safe when C2 connects to merely H atoms or merely substitutes. It is also safe while the chemical bonds between C2 and C3 or C3 an

37、d C4 are double bonds.。,Quantitative Structure-Activity Relationships (QSARs),It is often possible to quantify structure-activity relationship data by correlating into a regression equation(回归方程式) the biological property with one or more physicochemical properties of a set of analogous substances.,I

38、n quantitative structure-activity relationships (QSARs) chemical structure is transformed into quantitative numerical values that describe physicochemical properties relevant to a given biological activity.,Quantitative Structure-Activity Relationships (QSARs),Quantification of structure-activity re

39、lationships for a given series of substances depends, therefore, on the successful identification of one or more physicochemical properties correlating with the biological property. The physicochemical properties that correlate with the biological property are most likely related to the mechanism of

40、 biological activity, and are often referred to as descriptors of biological activity.,Quantitative Structure-Activity Relationships (QSARs),An example of a general QSAR equation is illustrated by equation :,log(1/C)=a(x)2 + b(x)+ c(y)+d,n r s,1/C: biological activity: (C is a standard concentration

41、 or dose of a substance required to elicit the biological activity) x n: number of substances r : correlation coefficient s : standard deviation of the regression.,Quantitative Structure-Activity Relationships (QSARs),The application of QSAR: delineate(描绘) the change in biological potency that is (o

42、r would be) accompanied by a given change in structure more precisely. For example using a QSAR correlation for acute lethality（致命性）, one can predict the median（中值的） lethal dose（致命剂量） (LD50) of an untested substance directly from a physical property of that substance.,Quantitative Structure-Activity

43、 Relationships (QSARs),The application of QSAR: it is not necessary to synthesize a substance in order to measure those physicochemical properties (Because there are methods for accurately estimating most physicochemical properties directly from structure),Quantitative Structure-Activity Relationshi

44、ps (QSARs),Shortly, one can estimate those properties, incorporate them into the appropriate QSAR regression equation and predict the biological property of the substance even though the substance does not exist! Medicinal chemists have, for many years, used QSAR as a tool for drug design. The U.S.

45、Environmental Protection Agency (EPA) has used QSAR since 1981 to predict the aquatic toxicity of new, untested commercial chemical substances in the absence of test data.,3.2 Designing Safer Chemicals Using Isosteric Replacements,Substances similar molecular and electronic characteristics have simi

46、lar physical or other properties. Langmuir called: Phenomenon: isosterism(电子等排同物理性质现象), m Compound: isostere(电子等排物). According to Langmuirs definition, isosteres are substances or substituents that have the same charge, caused by the same number and arrangement of electrons and the same number of at

47、oms.,Designing Safer Chemicals Using Isosteric Replacements,Based on molecular orbital theory, several variations of Langmuirs definition of isosterism were expressed by others. Burgers definition: isosterism also encompasses(包含) chemical substances, atoms or substituents that possess near equal or

48、similar molecular shape and volume, approximately the same distribution of electrons, and which exhibit similar physicochemical properties.,H and F OH and NH2 CH3 and SH and Cl CH2 and NH and Oand Sand SiH2 N= and CH and S In cyclic structure CH=CH and S and O and NH,Benzene is isosteric with thioph

49、ene and pyridine because the CH=CH- group is isosteric with -N= and -S- atoms,Although these substances are structurally different, some of their chemical properties are nonetheless similar. All of them are aromatic, all are liquid, and all are about equal in molecular size and volume. In fact, both

50、 12 and 41 boil at about 81 C.,Examples,7-Methyl-benzoaanthracene (7-甲基苯并蒽), is a known carcinogen.,7-methyl-l-fluorobenzoaanthracene (7-甲基-1-氟苯并蒽) is not .,It is also possible that biological properties may be bestowed(给予), exacerbated(恶化) or attenuated when isosteric modifications are made.,Acetic

51、 acid , on the other hand, is essentially nontoxic but its fluoro-isostere, fluoroacetic acid , is highly toxic (human oral LD50 is estimated to be 2-5 mg/kg CH3COOH FCH2COOH non toxic oral LD50 2-5 mg/kg,In the body acetic acid reacts with coenzyme A(辅酶A)(CoA) to form acetyl-CoA(乙酰辅酶A), which is an

52、 important precursor of the citric acid cycle(柠檬酸循环)(a biochemical cascade essential for energy production). Fluoroacetic acid is so sterically similar to acetic acid that it also reacts with CoA, and forms fluoroacetyl-CoA. Fluoroacetyl-CoA enters the citric acid cycle and forms fluorocitrate, whic

53、h is a potent inhibitor of aconitase(鸟头酸酶), a critical enzyme of the citric acid cycle,Example 3,Its potential as a useful anti-ulcer medication was lessened by the toxic effects caused by the thiourea（硫脲） moiety.,During the development of anti-ulcer(抗溃疡) medications, for example, it was found that

54、metiamide (麦角胺) greatly reduced acid secretion（分泌） in the gastrointestinal tract.,Isosteric replacement of the thiourea moiety with the cyanoquanidine（氰基胍）moiety gave cimetidine, a potent H2-receptor antagonist that lacks the toxicity of metiamide.,Cimetidine is one of the most widely used anti-ulce

55、r medications in the world because of its effectiveness in treating ulcers and relative safety.,It is noteworthy that in this example this isosteric modification selectively reduced toxicity without affecting pharmacological activity. This is a main reason why isosteric substitution is a common prac

56、tice among medicinal chemists for the design of drug products.,Metallized azo dyes(金属偶氮染料),Metallized azo dyes: Historically, chromium was a metal of choice in many metallized azo dyes because it imparts the desired color and fastness. Hexavalent chromium (Cr VI) was often used in making such dyes.

57、Hexavalent chromium is a known human carcinogen, however, and its commercial use is strictly regulated and highly discouraged by environmental authorities.,Metallized azo dyes(金属偶氮染料),An alternative metal to chromium in premetallized azo dyes would have to have the same color and fastness properties

58、 as chromium but without the toxicity. It has been found that iron (Fe), which is essentially nontoxic, often imparts the same desirable qualities as chromium when used in azo dyes. This is exemplified in comparing azo dyes. Dyestuff 50 has the same color and fastness as 49, but does not contain chr

59、omium. Other examples of dyestuffs that use iron rather than chromium are available,Designing Metallized azo dyes (金属偶氮染料的设计),M,M=Cr, toxic M=Fe, non-toxic,Example 4,MTI-800 is a potent insecticide that is also highly toxic to fish (its LC50 is 3 mg/liter), which limits its commercial usefulness.,MTI800 Fish LC50=3mg/ll,Isosteric substitution of the quaternary carbon with silicon resulted in a new substance that has moderately less insecticidal potency (0.2-0.6) b