绿色化学-第三章.PPT

Chapter 3The general principles and methods for designing safer and effective chemicals设计安全无毒化学品设计安全无毒化学品的基本原理和方法的基本原理和方法3.1 General principles for designing safer and effective chemicals 3.2 Techniques in designing of safer and effective chemicals3.1 General Principles for Designing Safer ChemicalsTwo main ways to avoid Hazard and Toxicity:l make it impossible to enter the body;l make it impossible to affect the bio-chemical and physiological processes(生物化学和生理过程)hazardously.nIt refers to,through molecular design,improving their physical and chemical properties which are relevent to environmental distribution and the up-take by living organisms,thereby reducing the harmful biological effects.FExternal considerations(“外部”效应原则）A.Properties related to environmental distribution/dispersion1.Volatility/density/melting point2.Water solubility3.Persistence/biodegradation a.oxidation,b.hydrolysis,c.microbial degradation 4.Conversion to biologically active substances5.Conversion to biologically inactive substancesB.Properties related to uptake by organisms1.Volatility2.Lipophilicity（亲油性）3.Molecular size4.Degradation a.hydrolysis（水解）,b.Effect of pH,c.susceptibility to digestive enzymes（消化酶）5.BioaccumulationBioaccumulation（生物集聚）or Bio-magnification(生物放大):It refers to the It refers to the increase of tissue increase of tissue concentration of a concentration of a chemical as it chemical as it progresses up the progresses up the food chain.food chain.C.Reduction/elimination of impurities1.Generation of impurities of different chemical classes2.Presence of toxic homologs（同系物）3.Presence of geometric,conformational or stereoisomers(几何、构象及光学异构体)F The internal considerations（“内部内部”效应原则）效应原则）They generally include approaches using molecular They generally include approaches using molecular manipulations to facilitate:manipulations to facilitate:bio-bio-detoxicationdetoxication（生物解毒性（生物解毒性););the avoidance of direct toxicitythe avoidance of direct toxicity（避免直接毒性（避免直接毒性););the avoidance of indirect bio-toxicity or bio-activation the avoidance of indirect bio-toxicity or bio-activation(避免生物活化避免生物活化).).A.Facilitation of detoxication or excretion(排泄）a.selection of hydrophilic(亲水的)compounds b.facilitation of conjugation with:glucuronic acid(葡萄糖醛酸)，sulfate(硫酸盐),amino acid(氨基酸）to accelerate urinary（泌尿的）or biliary(胆汁的)excretion.B.Avoidance of direct toxication1.Selection of non-toxic chemical classes；2.Selection of non-toxic functional groups.avoidance of toxic groups；planned biochemical elimination of toxic structure through the normal metabolism of the organism；structural blocking of toxic groups；alternative molecular sites for toxic groups.C.Avoidance of bioactiovation nBioactiovation(生物活化）describes the circumstances where a chemical is not toxic in its original structural form but becomes toxic after in vivo（在有机体内）transformation to a toxic metabolite（代谢物）.nBioactivation represents a characteristic mechanism for the toxicity of many carcinogenic(致癌的),mutagenic（诱变的）,and teratogenic（畸胎的）chemicals.Mechanistic toxicological research毒理学研究毒理学研究nResearch in toxicology must shift its emphasis to mechanistic research,or basic understanding of how a specific chemical or chemical class exerts its toxicological effect on living organisms at the molecular level.nIt is only with the accumulation of substantial data and information of this nature that the correlative principles and concepts of structure-activity relationship(SAR)can be developed further.Industrial efficacy of chemicalsIndustrial synthesis chemist Traditional Industrial educational modeMedical and pesticide chemistsPharmacological,Biochemical,Toxicological effects(SAR）TraditionalPharmacological educational modeNew hybrid Green chemistA comparison of the traditional educational mode and the new mode needed for cultivation of hybrid chemist3.2 Techniques in designing of safer and effective chemicals3.2.1 Toxicological mechanism and structural modifications of the molecule3.2.2 Designing safer chemicals using structure-activity (toxicity)relationships3.2.3 Designing safer chemicals using isosteric replacements3.2.4 Designing safer chemicals using retro-metabolic design3.2.5 Identification of equally useful,less toxic chemical substitutes of another class3.2.1 Toxicological mechanism and structural modifications of the moleculenToxic of chemicalsExposure Absorption,Distribution,MetabolismExcretionChemical-biologicalInteraction in target tissuesToxicToxicEffectEffect Intrinsic toxicity（固有毒性）the ability of a substance to cause an alteration in normal cellular（细胞的）biochemistry and physiology（生理学）following absorption.Toxicophore(毒性载体)a particular structural portion of the substance to which the toxicity is generally attributed.Toxicogenic structure（产毒结构):Some substances contain structural features that are not directly toxic but undergo metabolic conversion(bioactivation)to yield a toxicophore.chemicals cellular membranes cellular membranes of skin,lung and of skin,lung and gastrointestinal tractgastrointestinal tractbloodstreamcells of organs and tissuescells of organs and tissues1.AbsorptionThe membranes of all cells of the body,particularly those of the skin,the epithelial(上皮的)lining(衬)of the lung,the gastrointestinal tract,capillaries（毛细血管）,and organs,are composed chiefly of lipids(脂肪).Blood stream is aqueous（水性的）.Therefore,absorption of a chemical substance into the body and its ability to travel through the bloodstream(distribution)to the area of the body where the toxic response is elicited requires that the substance has a certain amount of both lipid solubility and water solubility.Physicochemical and biological factors influencing membrane permeation and absorptionBiological factorsRoute of Surface Thickness of Blood flowexposure area(m2)absorption barrier(m)(L/min.)Skin 1.8 100-1000 0.5Gastrointestinal 200 8-12 1.4 tract Lung 140 0.2-0.4 5.8Absorption by Gastrointestinal tract(肠胃系统）nThe gastrointestinal tract is a major site from which chemical substances are absorbed.For its largest absorbing surface area and the second greatest blood flow.nMany environmental toxicants enter the food chain and are absorbed together with food from the gastrointestinal tract.small intestines:pH=12large intestines:pH=8 nAcidic substances are absorbed more readily from the small intestines（pH=1-2),because they are less dissociated in the small intestines.n The opposite is true for basic substances（pH=8)absorbed in large intestines.nOther physicochemical properties:Physical state(liquid,solution,small grain)Solubility(certain aqueous solubility and good lipid solubility)Molecular weight(1000)Absorption from the lung（肺）nThe thickness of the alveola cellular membrane(the absorption barrier of the lung)is only 0.20.4m.nThe lungs also receive 100%of the blood pumped from the heart.nphysicochemical properties:Physical state(gas,small grain)Solubility(good aqueous solubility)solid size(1m)Skin Absorptionn For chemicals to be absorbed from the skin,they must pass through the 7 cell layers of the epidermis(表皮)before entering the blood.This absorption barrier ranges from 100 to 1000m.n The rate determining step is diffusion through the stratum corneum(horny layer,角质层),which is the uppermost layer of the epidermis.Passage through the 6 other layer is much more rapid.nphysicochemical properties:Physical state(liquid)Solubility(certain aqueous solubility and good lipid solubility)2.DistributionnDistribution refers to the movement of a chemical through the living system from its sites of entry into the bloodstream following absorption.nThe rate of distribution of organs or tissues is primarily determined by blood flow and the rate of diffusion out of the capillaries into the cells of a particular organ.nFollowing absorption,many substances distribute to the heart,liver,kidney,brain,and other organs.nFor example,substances that are not very lipophilic(亲脂性的）generally do not enter the brain because they cannot penetrate the blood-brain barrier,whereas substances that are more lipophlic are more likely to enter the brain.n Other factors,such as extent of binding to plasma proteins（血浆蛋白质）,and accumulations in fat tissues（脂肪组织）,are also dependent on physicochemical properties.3.Metabolism(代谢）nThe body has the ability to distinguish between non-food(foreign)chemical substances(e.g.,industrial chemicals,drugs)and nutritional substances(e.g.,vitamins,carbohydrates,amino acids).nThe body,however,has enzyme-catalyzed mechanisms(酶催化机制）for converting substances into more water soluble substances that are easier to excrete.These mechanisms are generally referred as metabolism（新陈代谢）or biotransformation（生物转化）.nThe purpose of metabolism detoxication:a defense mechanism to convert potentially toxic chemical substances to other substances(metabolites)that are readily excreted.nThe chemical reactions involve phase-or phase-reactionsnPhase-reactions convert the chemical substances into a more polar metabolite by oxidation,reduction,or hydrolysis.nPhase-reactions involve coupling(conjugation)of the chemical substance with an endogenous(内生的)substrate such as glucuronate(葡萄糖酸),sulfate（硫酸盐）,acetate（醋酸盐）,or an amino acid（氨基酸）,which further increases water solubility and promote excretion.nNote:Metabolism of certain chemical substances does not result in detoxication.nIn fact,it is the metabolites of many toxic chemical substances that,ironically,are responsible for the toxicity.4.Toxicodynamics（毒性动态学）nThe toxicodynamic phase comprises the processes involved in the molecular interaction between the toxic substance and its bio-molecular sites of action and the resultant sequence of biochemical and biophysical events that finally result in the observed toxic effect.nIn general,a toxic substance exerts its toxicity by the interaction of a particular portion of the molecule with a cellular macromolecule(enzymes酶,nucleic acids核酸,or protein蛋白质),which disrupts normal biochemical function of the macromolecule and ultimately results in the toxicity.What the particular portion is called What the particular portion is called as as?nDesigning safer chemicals from an under standing of toxic mechanism1.Toxic mechanisms involving electrophiles(亲电性物质)Chemical substances that are electrophilic or are metabolized to electrophilic species are capable of reacting covalently(发生共价结合）with nucleophilic substituents of cellular macromolecules such as DNA,RNA,enzymes,proteins,and others.n nThese These irreversible irreversible covalent covalent interactionsinteractions can can lead lead toto a a variety variety of of toxic toxic effects effects including including cancer,cancer,hepatotoxicityhepatotoxicity (肝肝中中毒毒),),hematotoxicityhematotoxicity(血血液液中中毒毒),),nephrotoxicitynephrotoxicity(肾肾 中中 毒毒),),reproductive reproductive toxicity,toxicity,and and developmental toxicity.developmental toxicity.n n nFortunately,the mammalian(哺乳动物)body has several defense systems that offer“sacrificial”nucleophiles（“自我牺牲”型亲 核 试 剂）that can react with foreign electrophiles.These natural defense systems are located predominately in the liver and among others,the glutathionetransferase system(谷膜甘肽转化酶)and the epoxide hydratase system（环氧化物水解酶）n Reactions of electrophiles with the nucleophiles of these systems form readily-excretable water soluble products,and allow the safe elimination of the electrophiles before they can react with the nucleophiles in the more biologically-critical cellular macromolecules.Electrophilicchemical substances Non-electrophilicChemicalsubstances Electrophilicchemical substancesReaction with nucleophiles withinNatural defense systems MetabolismNon-toxic,Water soluble adducts Reaction with nucleophilesof non-defenseCellular macromoleculesExcretionToxicity 2.Designing safer electrophilic substancesnIdeally,electrophilic substituents should never be incorporated into a substance.nHowever the electrophilic group is often necessary for the intended commercial use of the substance.Avoiding the interaction of the molecule with the cellular macromolecule in the tissues,thus reducing the toxicity（1）Decreasing the electrophilicity of the moleculesExample Acrylates(丙烯酸酯)CHCH2 2=CHCOOCH=CHCOOCH2 2CHCH3 3Carcinogenic(致癌致癌)Methacrylates(甲基丙烯酸酯甲基丙烯酸酯)CHCH2 2=C=C（CHCH3 3）COOCHCOOCH3 3Non-carcinogenic（2）electrophilic-masking approach The product is not readily fabricated directly and the electrophilic groups are masked by certain concealing agents(掩蔽剂）which will be removed when the product is want to be used.Example 1：isocyanates(异氰酸酯)R-N=C=OFollowing inhalation exposure many isocyanates are pneumotoxic(肺中毒),causing pulmonary sensitization(肺敏感)and asthma(肺气喘).Some isocyanates are believed to be mutagenic(变异）and carcinogenic（癌变）as well.To reduce the likelihood of isocyanate-induced toxicity,chemists mask the electrophilic character of this functional group by converting it into a ketoxime(酮肟)derivativeRNHCOON=C(CHRNHCOON=C(CH3 3)CH)CH2 2CHCH2 2CHCH2 2CHCH3 3The isocyanate-ketoxime is usually made in-situ during the manufacture of the isocyanate,thereby minimizing environmental and worker exposure to the isocyanate.nWhen ready to be used in coatings,the ketoxime moiety is removed thermally during application,thereby regenerating the isocyanate and enabling it to react with the intended nucleophile(usually an amine)without the risk of human exposure Example 2：vinyl sulfone(乙烯砜乙烯砜)The vinyl sulfone group is highly electrophilic and frequently used in fiber reactive dyes.R R R RSOSOSOSO2 2 2 2CHCHCHCH2 2 2 2CHCHCHCH2 2 2 2OH OH OH OH -hydroxyethylhydroxyethyl sulfonesulfone(-羟基乙砜羟基乙砜羟基乙砜羟基乙砜)+H H2 2SOSO4 4 R RSOSO2 2CHCH2 2CHCH2 2OSOOSO3 3-Strong baseR RSOSO2 2CHCH2 2CHCH2 2 The The vinyl vinyl sulfonesulfone needed is needed is regenerated regenerated in situin situ3.Toxic Mechanisms Involving Bioactivation to Electrophiles and the design of related molecule.vThe majority of biochemical reactions that lead to formation of electrophilic metabolites involve cytochrome(细胞色素)P450-catalyzed oxidations.vIn these reactions a particular portion of the molecule is bioactivated to become an electrophile.肝肝中中毒毒细胞色素亲核剂4.Examples of designing safer chemicals using toxic mechanismExample 1:Toluene instead of benzene Benzene can cause blood poisoning or leukemia 肝中毒肝中毒肝中毒肝中毒白血病白血病白血病白血病Toluene is relatively less toxic无毒无毒Example 2:Design a more secure two ether(二醇醚）Two ether can cause reproductive and developmental systems poisoning,for it generates toxic alkoxylate carboxylic acid under the action of the oxidase.R-O-CH2CH2OHR-O-CH2COOH有毒有毒R=CH3,C2H5,C4H9烷氧取代酸烷氧取代酸R-O-CH2CH(CH3)OHRCH=O+HOCH2CH(CH3)OH无毒无毒pharmacophore/toxicophore nIn the case of drugs,in which the biological response is desired,this structural feature is referred to genetically as the pharmacophorenIn the case of commercial chemical substances,in which the biological effect is undesired(toxic),the structural feature is referred to genetically as the toxicophore.3.2.2 Designing safer chemicals using structure-activity(toxicity)relati