Last Update: April, 2020 Grade: 12 Subject: Chemistry 30 Unit: Organic Chemistry Title: A Case Study - Improving Human Health Drug Action – Isomer’s Evil Twin? Rationale: Students will explore the nature of science with respect to organic molecules used in biomedical research, and will consider the intended and unintended consequences of the drug’s actions. Background Information: Research in the Derda Research Group at the University of Alberta is bridging synthetic organic chemistry and genetically-encoded libraries (a technology for creating a large library of small molecules used in medicinal chemistry) to solve fundamental problems in drug discovery, cell biology, and diagnosis of disease. Protein-carbohydrate interactions are the basis of cell-cell and cell-pathogen interaction. The Derda Research Group pioneered a powerful approach for genetically-encoded discovery of molecules that block or mimic protein-carbohydrate interactions. This approach is used to identify molecules that can be used as inhibitors of unwanted protein-carbohydrate interaction in drug-resistant tumors, new cancer immunotherapies, and as improved molecular diagnostics for tuberculosis. Once these molecules are identified, the nature of the isomer can be determined using X-Ray crystallography. Isomers will be investigated in this lesson. Curriculum Connections ● 30–C1.2k identify and describe significant organic compounds in daily life, demonstrating generalized knowledge of their origins and applications ● 30–C1.3k name and draw structural, condensed structural and line diagrams and formulas, using International Union of Pure and Applied Chemistry (IUPAC) nomenclature guidelines, for saturated and unsaturated aliphatic (including cyclic) and aromatic carbon compounds ● 30–C1.4k identify types of compounds from the hydroxyl, carboxyl, ester linkage and halogen functional groups, given the structural formula ● 30–C1.5k define structural isomerism as compounds having the same molecular formulas, but with different structural formulas, and relate the structures to variations in the properties of the isomers
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LastUpdate:April,2020
Grade:12 Subject:Chemistry30 Unit:OrganicChemistry
Title:ACaseStudy-ImprovingHumanHealthDrugAction–Isomer’sEvilTwin?
Rationale:Studentswillexplorethenatureofsciencewithrespecttoorganicmoleculesusedinbiomedicalresearch,andwillconsidertheintendedandunintendedconsequencesofthedrug’sactions.
BackgroundInformation:ResearchintheDerdaResearchGroupattheUniversityofAlbertaisbridgingsyntheticorganicchemistryandgenetically-encodedlibraries(atechnologyforcreatingalargelibraryofsmallmoleculesusedinmedicinalchemistry)tosolvefundamentalproblemsindrugdiscovery,cellbiology,anddiagnosisofdisease.Protein-carbohydrateinteractionsarethebasisofcell-cellandcell-pathogeninteraction.TheDerdaResearchGrouppioneeredapowerfulapproachforgenetically-encodeddiscoveryofmoleculesthatblockormimicprotein-carbohydrateinteractions.Thisapproachisusedtoidentifymoleculesthatcanbeusedasinhibitorsofunwantedprotein-carbohydrateinteractionindrug-resistanttumors,newcancerimmunotherapies,andasimprovedmoleculardiagnosticsfortuberculosis.Oncethesemoleculesareidentified,thenatureoftheisomercanbedeterminedusingX-Raycrystallography.Isomerswillbeinvestigatedinthislesson.
CurriculumConnections
● 30–C1.2kidentifyanddescribesignificantorganiccompoundsindailylife,demonstratinggeneralizedknowledgeoftheiroriginsandapplications
● 30–C1.3knameanddrawstructural,condensedstructuralandlinediagramsandformulas,usingInternationalUnionofPureandAppliedChemistry(IUPAC)nomenclatureguidelines,forsaturatedandunsaturatedaliphatic(includingcyclic)andaromaticcarboncompounds
● 30–C1.4kidentifytypesofcompoundsfromthehydroxyl,carboxyl,esterlinkageandhalogenfunctionalgroups,giventhestructuralformula
● 30–C1.5kdefinestructuralisomerismascompoundshavingthesamemolecularformulas,butwithdifferentstructuralformulas,andrelatethestructurestovariationsinthepropertiesoftheisomers
LastUpdate:April,2020
● 30–C2.3stsexplainhowscienceandtechnologyhavebothintendedandunintendedconsequencesforhumansandtheenvironment
LessonObjectives/Concepts
● Studentswillexploresignificantorganiccompoundsusedinbiomedicalresearch.● Studentswillexamineanorganicmoleculedeterminedtobeaproteininhibitorand
determinethemolecularformulaandstructuraldiagramgiventhelinediagram.● Studentswillidentifyfunctionalgroupsoftheorganicmoleculeprovided.● Studentswillinvestigateisomerismandrelatethestructurestointendedand
unintendedconsequences.
Materials:AccesstoYouTube,studenthandouts. Time:1classperiod.
Introduction(10minutes)1. Beginwiththeword,“Isomer”,anddirectstudentstotheetymologyoftheword(use
theonlineetymologydictionary).Discussthemeaningoftheword-fromGreekisomeres"sharingequality,havingequalpartsorshares"
2. ShowtheThalidomideTragedyAskstudentstothinkthroughthesequestionswhilewatching.“WhydoyouthinktheRetro-reportisentitled,“TheShadowofThalidomide”?”“Howhasdrugresearchortestingchangedbecauseofthisdisaster?”“Whatdoyouknowaboutthedrugsyouoryourfamilyuse?”
3. Explainthatdrugresearchtodayisfarmorerigorousanditallbeginswithcarefulinvestigationoftheorganicchemistryofmolecules.StudentswillinvestigateasmallmoleculecurrentlybeingusedinthecreationofanorganicmoleculelibrarybeingdevelopedattheUniversityofAlberta.
Activities/Procedure(50minutes)Pre-teaching,doneinadvanceofthislessonEnsureyouhavereviewedtheintermolecularforcesofLondondispersion,dipole-dipole,andhydrogenbondingbeforeyoubeginthislesson.AllmoleculeshaveLondondispersionforceswhicharetemporaryinduceddipolesduetothemovementofelectronsinmolecules.Thelargerthemolecules,themoresignificanttheLondonforces.Moleculeswillonlyexhibitdipole-dipoleforcesiftheyarepolarmolecules.Moleculeswillonlyexhibithydrogenbondingifthemoleculecontainsahydrogenatomcovalentlybondedtooneofnitrogen,oxygen,orfluorine.LessonStudentswillbeprovidedwithalinediagramofamoleculecurrentlybeingusedinresearch.
LastUpdate:April,2020
Studentswillanalyzethemoleculetodeterminethemolecularformula,structuralformula,identifyfunctionalgroupsandtheirformulas,andpredictintermolecularattractions.IfyouareteachingIBorAP,youcanencouragestudentstolookforfunctionalgroupscontainingnitrogen-aminesandamides.Thiscanalsobeusedasextensionmaterial.Amine:Amide:Studentswilllookatisomerismwithrespecttodrugdevelopmentandresearchandresearchthesocialandscientificissues.
Summary:Askstudentstogetintogroupsoffourwhereeachmemberstudiedadifferentdrug.Studentstaketurnssummarizingtheintendedandunintendedconsequencesoftheresearcheddrugaction.Asasocietalperspectiveonovercomingchallenges,showtheYouTubevideo,“AlvinLaw–SurvivingHighSchool”whichshowcasesaCanadianmanaffectedbythalidomide.
Assessment:Usetheprovidedanswerstoassessstudentwork.
Extensions/Connections:IBandAPchemistry-discussthenatureandstructureofstereoisomers.Inpairs,askstudentstoresearchanddiscussstereoisomersandthenattempttodrawthethalidomideisomerswiththemolecularmodelkits.Beginwiththeconceptofmirrorimagesandhowitisimpossibletosuperimposeyourhandsontopofeachother.Theyareotherwiseidentical.Thiswasthecasewiththeactiveandinactiveformofthalidomide.
Image:WikimediaCommons,https://goo.gl/yt2uQeThalidomideisomersareshownatright:Image:WikimediaCommons,https://goo.gl/cfnD9V
LastUpdate:April,2020
AnswerKey1.Determinethemolecularformulaforthemoleculeontheleft(geneticallyencodedpeptide).
Image:DerdaResearchGroup
MolecularFormula:C16H24N5O7R32.Circletwofunctionalgroupsfoundonthemolecule.Completethetablebelow.
FunctionalGroupName FunctionalGroupFormula
carbonyl CO
carboxyl COO-
LastUpdate:April,2020
Extension:Amine NH2
Extension:Amide CONH
3.Whatintermolecularforceswillthefunctionalgroupshave?
FunctionalGroupName TypeofIntermolecularforce
carbonyl Londondispersion,dipole-dipoleAllmoleculeshaveLondondispersionforcesasallmoleculeshaveprotonsandelectronsthanattractothermoleculesprotonsandelectrons.Moleculesthatcontainacarbonylgroupwillbepolarandwillthenhavedipole-dipoleforces.
carboxyl Londondispersion,dipole-dipole,hydrogenbondingMoleculesthathaveahydrogenatomcovalentlybondedtoanoxygenwillbeabletohydrogenbondwithothermolecules.
Extension:amine Londondispersion,dipole-dipole,hydrogenbonding
Extension:amide Londondispersion,dipole-dipole,hydrogenbonding
4.Moleculeswillbondtoproteinsinanefforttoinhibitthatprotein.Thebondswillbeeitherionic(chargeattraction),orintermolecular.Thepartoftheproteinthatamoleculewillbondtoiscalleda“bindingsite”andisshownastheopenspacebelow.Themoleculewill“fit”intheopenspaceoftheprotein.Basedonthisspecific“bindingsite”,whattypeofbondingwouldyousuggestwouldoccur?Substantiateyouranswer.
LastUpdate:April,2020
Image:MolecularBiologyofTheCell4thEdition(2002)AnyNH2groupfromthemoleculewillhydrogenbondtotheanyoftheoxygenornitrogenlonepairsinthebindingsite(aslongastheoxygenornitrogeniscovalentlybondedtothehydrogen)asseenbyoneexampleshownasthesquigglylineabove.TheCOO-groupfromthemoleculewillhaveachargeattraction(ionic–positivetonegative)totheNH2
+group.Thesearetwopossibilities.5.Manyorganicmoleculescanformisomers.Drugs,suchasthalidomide,canhaveintendedandunintendedconsequences.Foroneofthefollowingdrugs,researchthestructuralformula,possibleisomers,describetheintendeddrugaction,andexplainifthereareanyunintendedconsequencesasaresultofthedevelopment.
Molecule Formula Isomers Drugaction Unintendedactions
quinine C20H24N2O2
quininehasantimalarialactivity
quinidinehasanantiarrythmicproperty
nebivolol C22H25F2NO4
NebivololD-isomerhashighlyselectivelybeta-1-blockingeffects,
L-isomerscausesvasodilatation
LastUpdate:April,2020
ibuprofen C13H18O2
S-ibuprofenisactiveform
R-ibuprofenisinactive
levomethorphan C18H25NO
Levomethorphanisapotentopioidanalgesic
dextromethorphanisacoughsuppressant
6.The“EvilTwin”ofthalidomideisnowbeingusedasananticancerdrug.Researchhowthisisomeractsandwhyitisnowbeingusedtobattlecancer.HowhasthisdisasteraffectedthewayresearchhaschangedintheUSandCanada?Actionof“EvilTwin”–AccordingtotheDana–FarberCancerInstitute(http://goo.gl/2QICrK)“researchersdemonstratedthatlenalidomide—amorepowerfulderivativeofthalidomide—killedmultiplemyelomacellsbydisablingoveractiveswitchescalledtranscriptionfactorsthatdrivethecells'excessivegrowth.Transcriptionfactorsareproteinsthatbindtogenesandincreasetheiractivity,andcancersareoftendrivenbyoveractivityofthesemolecularswitches.”ResearchRigour:AccordingtoFDAVoice(http://goo.gl/Vmvi5)“Inresponsetothepublicuproar,in1962CongressenactedtheKefauver-HarrisamendmentstotheFederalFood,DrugandCosmeticAct.Thankstothesenewamendments,manufacturershadtoprovethatadrugwasnotonlysafe,butalsoeffective.Approvalshadtobebasedonsoundscience.Companieshadtomonitorsafetyreportsthatemergedpost-marketandadheretogoodmanufacturingpracticesthatwouldleadtoconsistentlysafeproducts.Andtherewerenewprotectionsforpatients.Theamendmentsnotonlybenefitedpatients,theyhelpedindustry,raisingscientificstandardsthateventuallyusheredintoday’ssophisticated,science-basedlifesciencesindustry.”
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