天然药物化学Word格式文档下载.docx
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天然药物化学Word格式文档下载.docx
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•医药是人类用以同疾病作斗争的一大类武器,亦即用以预防、治疗和诊断疾病的物质。
•目前,临床用药物主要有五大来源,即发酵法、化学合成法、生化法、动物脏器及植物提取法。
DrugDevelopmentandProduction-aHistoricalOutline
•Sinceancienttimes,thepeoplesoftheworldhaveusedawiderangeofnaturalproductsformedicinalpurposes.Theseproducts,obtainedfromanimal,vegetableandmineralsource,weresometimesveryeffective.However,manyoftheproductswereverytoxic.Informmationabouttheseancientremedieswasnotreadilyavailabletousersuntiltheinventionoftheprintingpressinthe15thcentury.Theinventionledtothewidespreadpublicationandcirculationofherbalandpharmacopoeias.Thisresultedinarapidincreaseintheuse,andmisuse,ofherbalandotherremedies.
•However,impovedcommunicationsbetweenpractitionersinthe18thand19thcenturiesresultedintheprogressiveremovelofpreparationsthatwereeitherineffectiveortootoxicfromherbalsandpharmacopoeias.Itasloledtoamorerationaldevelopmentofnewdrugs.Initiallythisdevelopmentwascenteredaroundthenaturalproductsisolatedfromplantandanimalmaterial,butasknowledgeincreasedawiderrangeofpharmaceuticallyactivecompoundsonwhichadevelopmentisbasedarenowknownasleadcompounds,whilethesyntheticcompoundsdevelopmentaleadarereferredtoasitsanalogue.
•Theworkofthemedicinalchemistiscentereredaroundthediscoveryofnewleadcompoundswithspecificmedicalproperties.Itincludesthedevelopmentofmoreeffectiveandsaferanaloguesfromboththesenewandexistingleadcompounds.Thisusuallyinvolvessynthesizingandtestingmanyhundredsofcompoundsbeforeasuitablecompoundisproduced.Itiscurrentlyestimatedthatforevery10,000compoundssynthesizedoneissuitableformedicaluse.
•ThefirstrationaldevelopmentofsyntheticdrugswascarriedoutbyPaulEhrlichandSacachiroHata,whoproductedtheantiprotozoal(止痒剂)arsphemamine(胂凡纳明)in1910bycombiningsynthesiswithreliablebiologicalscreeningandevaluationprocedures.Ehrlich,atthebeginningofthe20thcentury,hadrecognizedthatboththebeneficialandtoxicpropertiesofadrugwereimportanttoitsevaluation.Herealizedthatthemoreaffectivedrugsshowedagreaterselectivityforthetargetmicroorganismthanitshost.Consequently,tocomparetheeffectivenessofdifferentcompounds,heexpressedadrug’sselectivity,andhenceitseffectiveness,intermsofitschemotherapeuticindex,whichhedefinedas
chemotherapeuticindex,whichhedefinedas
•Determinationandcatalogingofthechemotherapeuticindexofthe60compoundsEhrlichandHatasynthesizedenabledin1909todiscoverarsphemamine(Salvarsan).ThisdrugasverytoxicbutsaferthanthethencurentlyusedAtoxyl(氨基苯胂酸钠).Itwasuseduptothemid-1940s,whenitwasreplacedbypenicillin.
•Today,Ehrlich’schemotherapeuticindexhasbeenupdatedtotakeintoaccountthevariabilityofindividualsandisnowdefinedasitsreciprocal,thetherapeuticindexorratio:
•Intheory,thelargeradrug’stherapeuicindex,thegreaterisitsmarginofsafety.Howecer,inpracticeindexvaluescanonlybeusedasalimitedguidetotherelativeusefulnessofdifferentcompounds.Thetermstucture-activityrelationship(SAR)isnowusedtodescibe.Ehrlich’sapproachtodrugdiscovery,whichconsistedofsynthesizingandtestingaseriedofstructurallyrelatedcompounds
•Attemptstoquantitativelyrelatechemicalstructuretobiologicalactionwerefirstintiatedinthe19thcentury,butitwasnotuntilthe1960sthatHanschandFujitadevisedamethodthatsuccessfullyincorporatedquantitativemeasurementsintoSARdeterminations.ThetechniqueisreferredtoasQSAR(quantitativestructure-activityrelationships).Oneofitsmostsuccessfuluseshasbeeninthedevelopmentinthe1970sofantiulceragentscimetidine(甲氰咪胍)andranitidine.BothSARSandQSARSareimportantpartsofthefoundationsofmedicinalchemistry.
•AnalternativeapproachtodrugsdesignwasinitiatedbytheworkofJohnLangley.In1905heproposedthatsocalledreceptivesubstancesinthebodycouldacecpteitherastimulatingcompound,whichwouldcauseabiologicalreponse,oranon-stimulatingcompound,whichwouldpreventabiologicalreponse.Itisnowuniversallyacceptedthatthebindingofachemicalagent.Referredtoasaligand,toasocalledreceptorsetsinmotioninmotionofaseriesofbiochemicaleventsthatresultinabiologicalorpharmacologicaleffect.
•Furthermore,adrugismosteffectivewhenitsstrutureorasignificantpartofitsstructure,bothasregardsmolecularshapeandelectrondistribution(stereoelectronic立体电子的structure),iscomplementarywiththestereoelectronicstructureofthereceptorresponsibleforthedesiredbiologicalaction.Thesectionofthestructureofaligandthatbindstoareceptorisknownasitspharmacophore.Futhermore,itisnowbelievedthatsideeffectscanarisewhenthedrugbindstoeitherthereceptorresponsibleforthedesiredbiologicalreponseortodifferentreceptors.
•Themid-tolate20thcenturyhasseenanexplosionofourunderstandingofthechemistryofdiseasestates,biologicalstructureandprocesses.Thisincreaseinknowledegehasgivenmedicinalchemistsaclearerpictureofhowdrugsaredistributedthroughthebodyandtransportedacrossmembranesandtheirmodeofoperationandmetabolism,Ithasenabledmedicinalchemiststoplacegroupsthatinfluenceabsorption,stabilityinabio-system,distribution,metabolismandexcertioninthemolecularstructureofadrug.
•Forexample,theintroductionofasulphonicacidgroupintostructureofadrugwillincreaseitswatersolubility.Thismayimproveitsabsorptionand/oritsrateofexcretionfromthebody.However,becauseofthecomplexnatureofbiologicalsystems,thereisalwaysadegreeofuncertaintyinpredictingtheeffectofstructuralchangesontheactivityofadrug.Asaresult,itisalwaysnecessarytocarryoutextensivetestingtodeterminetheconsequencesofmodifyingastructure.
Furthermore,changingagrouporintroducingagroupmaychangethenatureoftheactivityofthecompound.Forexample,thechangeoftheestergroupinprocaine(普鲁卡因)toanamide(procainamide)changestheactivityfromalocalanaesthetic(麻醉剂)toantirhythmic.
•Theintroductionorremovalofchargedgroupsorgroupsthatcanformionsontooroutofastructuremaybealsohavemarkedaffectondrugaction.Thisisbecausedrugsnormallyhavetocrossnonpolarlipidmembranebarriersinordertoreachtheirsiteofaction.Consequently,asthepolarnatureofthedrugincreases,ituusualybecomesmoredifficultforthatdrugtocrossthesebarriers.Forexample,quatermaryammoniumsalts,whicharepermanentlycharged,canbeusedasanalternativetoanamineinastructureinordertorestrictthepassageofadrugacrossamembrane.Thestructureoftheanticholinesterase(抗胆碱酶)neostigmine(新斯的明).developedfromphysostigmine(毒扁豆碱),containsaquaternaryammoniumgroup.Whichstopsthemoleculefromcrossingtheblood-brainbarrier.ThispreventsunwantedCNSactivity.However,itsanaloguemiotinecanformthefreebase.Asaresult,itisabletoacrosslipidmembrances,whichmaycauseunwantedCNSsideeffects.
•Computermodelinghasreducedtheneedtosynthesizeeveryanalogueofaleadcompound.Itisalsooftenusedretrospectivelytoconfirmtheinformationderivedfromotherbinatorialchemistry.whichoriginatedinthefieldofpeptidechemistry,hasnowbeenexpandedtocoverotherarears.Thetermcoversagroupofrelatedtechniquesforthesimultaneousproductionoflargenumberofcompoundsforbiologicaltesting.Consquently,itisusedforstructrueactionstudiesandtodiscovernewleadcompounds.Theproceduresmaybeautomated.
医药分类
•医药按药理作用分为心血管系统药物、抗菌药物(包括抗生素)、抗精神失常药、抗炎解热镇痛药、消化系统药物、抗癌药、呼吸系统药、麻醉药、催眠药和镇静药、抗癫痫药、抗组织胺药、利尿脱水药、脑血管障碍治疗药、抗寄生虫药、降血糖药、维生素类药、激素类药等
2.Classificationofdrugs
•Drugsareclassifiedinanumberofdifferentwaysdependingonwhereandhowthedrugsareused.Themetheodsofmostinteresttomedicinalchemistsarechemicalstructrueandpharmacologicalaction,whichincludesthesiteofactionandtargetsystem.Unfortunately,classifyingdrugsaccordingtotheirchemicalstructuretypehasthedisadvantagethatmembersofthesamestructuralgroupoftenexhibitverydifferenttypesofpharmacologicalactivity.Steroids,forexample,mayactashormones(testoterone),diuretics(spironolactonezan安体舒酮)actibacterialagents(fusidicacid梭链孢酸)amongstotherformsofactivity.
•Thetermprodrugisoftenusedfordrugswhoseactiveformisproducedbyenzymeorchemicalactionatorneartoitssiteofaction.However,itisemphasizedthatotherclassification,suchasthenatureoftheillnessandthebodysystemonwhichthedrugacts(physiologicalclassification),arealsousedinmedicinalchemistryaswellasotherfieldsdependingonthepurposeoftheinformation.
•thedrugsmanufacturedtodaycanbegroupedintocertainmainclasses.Theseclassesdonotcoveralldrugsbutdoincludemostofthosewhicharewidelyused.Thepharmaceuticalindustrynotonlyproducesdrugproductsthathavewideapplication,butasaservicetomedicinealsohasmadecertaindrugsavailable,oftenatconsiderablecost,forthetreatmentofinfrequentspecialconditionssuchasironpoisoning,botulism(波特淋菌),snakebite.
•Representativecompoundsinthecategoriesdescribedbelowaretoillustratethevarioustypesofchemicalstructurepresentindrugproducts.
2.1Analgesics
•Thistypeofannalgesicisusedforthereliefofmildpain.Examplesareaspirin,acetaminophen,andphenacetin
2.2Antacides抗酸剂
•Gastricantacidsareagentsthatneutralizeorremoveacidfromthegastriccontents.Generallytheycontainawe
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