生物活性分子的结构及作用(英文)课件

KJM5230-Biologiskaktivemolekyler(BioactiveMolecules)Thecourcediscusstheorganicchemistryofimportantclassesofdrugsandbioactivenaturalproducts.Synthesis/biosynthesis,modeofaction,bioavailabilityandstabilityforchosendrugclasses.StructureactivityandstructureoptimalisationKJM5230-H06NaturalProductsDrugDesignReseptors-DrugActionDrugMetabolismAntibiotics/AntimicrobialAgentsAntiparasiticAgentsAntifungalAgentsAntimycobacterialAgentsAnticancerAgentsAntiviralAgentsKJM5230-H06OriginofDrugs/BioactiveCompoundsNaturalProducts/NaturalProductDerivativesRandomtesting,serendipity*ScreeningofLibraries(Rational)DrugDesign(1.mentionedSciFinder1970,mostpapersafter1990)Screening/Design/SerendipityLeadcompound-Design/StructureOptimisationActualDrugWhynewdrugs?

Resistance Newdiseases(Aging,lifestyle) LesstolleranceforsideeffectsActivityToxicityBioavailabilityMetabolisminvitroinvivoanimalsinvivohumans*Fortunatediscoverybyaccident“ThethreeprincesofSerendip”PersianFairytail

Serendip=SriLankaKJM5230-H06OriginofDrugs/BioactiveCompounds:HistoryBefore1800:Plants,plantextracts,inorganicmaterial1805:Morphineisolatedfromopium(sructureproposed1935,proovedbysynth.1952)1828:Firstorganicsynthesis(urea)1840-1850:Firstsynthesizedorg.compdsusedinmedicine:CHCl3,Et2Oanestechia)Exofearlysyntheticdrugs: Choralhydrate(sleepingpill)1869 Acetylsalicylicacidsynth1853,clintrials1893

Phenazonesynth1884 Benzocaine1902 Prontocil1932

Exofearlyisolatednat.prod. Quinineca1825 Digitoxin1841(structure1928) Salicylicacid,antipyretic1875 Cocaineisol.1860,localanestethic1884 Benzylpenicillin1941TraditionalmedicineScreeningSerendipityKJM5230-H06NaturalProductsOnlysourceofdrugsbeforelastpartof19thcenturyAntibiotics1940-1960Cyclosporin(immunomodulator)isolatedfromsoilfungusHardangervidda1971Taxolisolated1960s,approveddrugUSA1992LeadcompoundsKJM5230-H06NaturalProductsSourcesMicroorganisms(bacteria,fungus)-AntibioticsHigherplants,ex.morphine,quinine,taxolSponges(polycellular“animals”,norealorgansorcelltissue)ex.agelasinesHigheranimals,fewerexamples,epibatidinefromSouthAmericantreefrogMicroorganisms,sponges,plantsNoimmunesystem,producetheirownantibioticsasdefenceSecondarymetaboliteswithgreatstructuraldiversity,stereochemistry!SecondarymetaboliteshavenoknownmetabolicroleincellsThreemainclasses:alkaloids,terpenoids,phenolicsKJM5230-H06AlkaloidNaturalProductsLargetsclassofsecondarymetabolites,

>6500compdsknownContainsN,mostcompdsbasic(alkaline)OftenhighlytoxicFoundincertainhigherplants(seldominbacteria)LittleisknownregardingwhyalkaloidesareproducedBiosynthesisfromaminoacidsKJM5230-H06SubtypescholinergereseptorsNicotinergeMuscarinergeSourceAmanitamuscariaNicotinefromNicotianatabacumAcetylcholineAlkaloidNaturalProductsAminoalkaloids:Nasamine/amide(notinheterocycle)Source

EphedrasinicaAlkaloidNaturalProductsAminoalkaloidsSourceLophophorawilliamsiPyridine/piperidinealkaloidsCocaineSourceErythroxyloncocaKJM5230-H06Parasympatolytika(Antikolinergika)TropanalkaloidsAtropabelladonnaHyoscamusniger(bulmeurt)SourceAtropabelladonna

og

HyoscamusnigerMusclerelax(guts,eye)ScopolaminPyridine/piperidinealkaloidsKJM5230-H06AlkaloidNaturalProductsCurare-Poison-SouthamericanindiansMixt.ofalkaloidsSeveralsourcesi.e.ChondodendrontomentosumIsoquinolinealkaloidsEx.

MivacuriumkloridMusclerelax,anesthesiaSuksametonium,Curacit®“Nesset”KJM5230-H06AlkaloidNaturalProductsIsoquinolinealkaloidsMorfinisolertfraopium1803(Morpheus:gresksøvngud)Morfinanalogs,bindstoopiopeptide(endorfin/enkefalin)reseptorsKJM5230-H06NaturallyoccuringandsemisynthanalgeticopioidesMorphineCodeinealsoagainstcoughslowmetabol.tomorphineSmallamountsinopium,semisynthfrommorphineKJM5230-H06TotalsyntheticanalgeticopioidesSAR-morphineModelofmorphineboundtom-reseptorKetobemidonKetodur®,Ketorax®Ketogan®FenantylFenantyl®,Leptanal®(anestetica)Petidin(Meperidin)Ketodur®,Ketorax®MoscowtheatreKJM5230-H06BuprenorfinTemgesic®,Subutex®MorepotentthanM.(pain)Partiellm-agonist:Antagonister

highdosesNaloxoneffects(dysforietc)DekstropropoksyfenAporex®(+)mostactivelessadict.thanM.m-Agonistanalgetc,noteuphoria,LongdurationGoodoralavailabil.MetadonKJM5230-H06BiosyntheticroutesinPapaversomniferumCodeineNoskapin(notanalgetic,notadiction)NaturallyoccuringandantitussivaopioidesEtylmorfinCosylan®HydrokonHydrokon®FolkodinTuxi®KJM5230-H06AlkaloidNaturalProductsQuinolinealkaloidsCinchonapubescens(Kinatre)fromSouthAmericaR=OMe:Quinine(CinchonidineepimeratC-9)R=H:Quinidine(CinchonineepimeratC-9)Quinidine:AntiarytmicQuinine:AntimalariaDihydroquini(di)neandder.ChiralligandsAsym.dihydroxylation(Sharpless)KJM5230-H06AlkaloidNaturalProductsIndolealkaloidsIndolenaturalproductsKJM5230-H06Strychnosalkaloids-fromStrychnosnuxvomicaKJM5230-H06TerpenoideNaturalProductsC-10:MonoterpenesC-15:SesquiterpenesC-20:DiterpenesC-25:SesterterpenesC-30:TriterpenesNaturesleavinggroupKJM5230-H06MonoterpenesVoilatilecompds,smell,tasteetc.TheChiralPoolPermetrin,Nix®Shampoo,Lice,scabiesCannabinoids,fromCannabissativa(Hemp)KJM5230-H06Diterpenes(C-20)HeadtotailcouplingKJM5230-H06Triterpenes(C-20)KJM5230-H06StereoidsB/CogC/Dalwaystrans(animals)CholesterolSexhormones Estrogens

Progesterones TestosteronandanabolicstereoidsCorticoids

Glucocorticostereoids Cortisonetc.etc. Mineralcorticostereoidsr AldosteroneDigitalisglycosidesFucidinicacid(antibiotic)Brassinostereoids(Plantgrowthhormones)etc.etc.KJM5230-H06Sexhormones-EstrogenesEstrogeneagonists(mimics)Phytoestrogen(insoya)KJM5230-H06Sexhormones-Progesterones(gestagenes,progestrines)Manysemisynthdrugsinuse(betterbioavalabil.)TestosteroneDoping-AnabolicstereoidsKJM5230-H06SemisynthesissexhormonesKJM5230-H06CorticostereoidsMineralcorticoidAldosteroneRegulationofelektrolytticballanceincreasere-uptakeofNa(andhenceH20)GlucocorticoidEffectonmetabolism(karbohydrates,lipids,proteins)AntiinflammatoricNumeroussemisynth.analogsasdrugsVariousantiinflam.activity,mineralcorticoidsideeffectsKJM5230-H06Digitalisglycosides(cardenolides)Digitalispurpurea

(foxglowe,revebjelle)-Treatmentofhartdisease1500BC(Egypt)-Increas