藥學專業(yè)英語視聽說教程 課件 視聽說上篇Lecture 6 Medicinal Chemistry

Lecture6MedicinalChemistryenantiomerprodruglipophilicityalkylatecycloadditioninterdisciplinaryesteramidekinasehydrolyticdrugdesignsmall-moleculedrugschemotherapeuticrefiningdrug-likeagentspreclinicalsyntheticorganicchemistrycombinepharmacokineticspharmacodynamics1.Threewaystoimprovethetherapeuticefficacyofadrug:1)Thebiologicalapproachto__________________________________________;2)Thephysicalapproachto____________________________________________;3)Thechemicalapproachto___________________________________________.2.Theidealpropertiesofaprodrug:1)Drugandthecarrierlinkagemustbe___________________________________;2)Itshouldnothave_________________________________________________;3)Itshouldrapidly___________________________________________________;4)Themetabolicfragmentsshouldbe____________________________________.altertherouteofadministrationmodifythedesignofthedosageformenhancedrugselectivityandminimizetoxicityclearedinvivointrinsicpharmacologicalactivitytransformintotheactiveformnon-toxic3.Characteristicsofthecarrierlinkedprodrugs:?Structure—_________________________________________________________________________________________________________?Chemicalnature—________________________________________?Mechanismofreleasingtheactivedrug—______________________ortransportmoietytheactivedrugbeingcovalentlylinkedtoaninertcarrierestersoramideswithgreatlymodifiedlipophilicityhydrolyticcleavage()1.Manydrugsarechiralmoleculeswithatleastonechiralitycenter,existinginenantiomerswhicharemirrorimagestoeachother.()2.Itispossibletosynthesizeonlyoneenantiomerofachiraldrugwithoutsynthesizingtheotherenantiomeratthesametime.()3.Itisverycommonthatbothenantiomersofachiraldrugarebiologicallyactiveandhavedesirableeffectonourbody.()4.Onlyoneoftheenantiomersofthalidomidewasusefulintreatingmorningsicknessandtheothercausedveryseverebirthdefects.()5.Chemistsareabletoisolatethetwoisomersofthalidomidefromeachothersothatonlythegoodenantiomerisprovidedtopregnantwomentoeliminatetheriskofbirthdefects.()6.Ibuprofencanbetakenintheformofamixtureoftwoenantiomerssincethebodycanconverttheharmfulonetothegoodone.TFFTFF1.WhyisSTAT3consideredanappealingtargetforthedevelopmentofanti-cancerdrugs?A.Becauseitpromotescancercellstodie.B.Becauseitcanactivatesignaltransductionincancercells.C.Becausetheknockoutofthisproteincanleadtoapoptosisofcancercells.D.Becauseitcanshutdownsignaltransductionincancercells.2.WhichofthefollowingisNOTtrueaboutthebindingbetweenananti-cancerdrugmoleculeanditstarget?A.Itshouldbeselectivesothatthedrugwon’tbindtoothermoleculesinhumanbody.B.Itshouldbepotentbecausewewanttokillcancercellswiththeuseofthesmallestpossibleamountofthedrug.C.Itshouldresultinabiologicalresponsethatcankillthecancercells.D.Itshouldoccurinaone-in-a-millionchance.3.WhatistheideaproposedbythespeakerfortargetingSTAT3?A.TodesigndrugmoleculesthatcandestroytheDNAboundinthemiddleoftheproteindimer.B.TodesigndrugmoleculesthatcanbindtoSTAT3anddisrupttheformationofdimer.C.TodesigndrugmoleculesthatcanactivatetheSTAT3dimer.D.TodesigndrugmoleculesthatpromotetheinteractionbetweenthetwomonomersofSTAT3dimer.4.WhatisthemajorproblemwithCompound1?A.Itistoopotent.B.Itistootoxic.C.Itistoolargeinmolecularsize.D.Itisnoteffectiveenough.5.WhatwasthestrategyadoptedtooptimizeCompound1?A.ToaddchemicalgroupssothatitbetterfitsintothetoppocketofSTAT3.B.Tomakeapocketinitschemicalstructure.C.Totailorthetoppartofthemolecule.D.Tousejigsawpuzzletodecidetheparttobechanged.1.HowwasCompound1optimizedinastepwisemannertogetalowIC50?OneoxygenincompoundIwasfirstreplacedwithanitrogen,buttheIC50valueincreasedhorribly.Thenabenzylgroupwasadded,theIC50decreasedto300μM.Thebenzylgroupwasfurthermodifiedintopara-cyano,tert-butyl,bi-phenolandcyclohexylbenzyl,resultingincontinuouslydecreasedIC50of260,190,115and4μMrespectively.Thecompoundwithcyclohexylbenzylwastwentytimesmoreactivethanthefirstmolecule.SomemorechangesweremadetothiscompoundandledtocompoundBP-1-102withanIC50of0.8μM.2.HowdidtheresearchersprovethatmoleculeBP-1-102wason-targetatcellularlevel?NokillingeffectwasfoundinhealthycellswhichdonnotcontainSTAT3.WhenaddedintothecultureoftumorcellswhichhadSTAT3,thecompoundkilledthesecellsnicely.Withincreasingconcentrationsofdrug,theamountofSTAT3wasdecreased,indicatingtheexistenceofdose-effectrelationship.3.WhathappenedwhenmoleculeBP-1-102wastestedinmice?Andwhatimprovementswerefurthermadetothismolecule?Wheninjectedintothemouse,thedrugwasgonewithin10minutesduetoextensivemetabolisminliver.Inaddition,itsstructurechangedcompletely,losingtheabilitytofitintotheproteintargetanymore-Thosepartsofthemoleculethatareconsideredweaktometabolicenzymeswerestabilizedthroughchemicalmethods.-Finally,aderivativeofBP-1-102withahalf-lifeofover4