优秀学术报告示例(Ari-Koskinen)PPT课件

1、2021/7/231Chemistry in Biomedicineand Drug DiscoveryProfessor Ari KoskinenHelsinki University of Technology11.03.20052021/7/232Ari KoskinenLaboratory of Organic Chemistry2021/7/2332021/7/234NumberapprovedbyFDA,024,021,718,616,215,513,712,51189,48,27,66,55,84,$/No.New Chemical Entities vs. R&D Ex

2、pedinture$ billions600,705040302010086 87 88 89 90 91 92 93 94 95 96 97 98 990,600,500,400,300,200,100,00R&D Spending $billionsNew molecularentities approved byFDARatio: $ / No.Note: Ethical pharmaceuticals only. Expenditures worldwide by U.S.-owned research-based pharmaceutical companiesC&E

3、N January 17, 2000, Food & Drug Administration,Pharmaceutical Research & Manufacturers of America: PhRMA Annual Survey 2000.Ari KoskinenLaboratory of Organic Chemistry2021/7/235New Drug DevelopmentAri KoskinenLaboratory of Organic Chemistry2021/7/236R&D By Geographic Area; 2001AfricaAmer

4、icasEuropeAsia-PacificAustraliaMiddle EastOthersAri KoskinenLaboratory of Organic Chemistry2021/7/237ab$ 1.7 bn (2003) per product is spent onR&D StageSynthesis/extractionBiological screening/pharmacological testingToxicology/safetyDosage formulationClinical evaluationProcess development formanu

5、facturing/ qualitycontrolRegulatoryOther% of spendinga11.016.06.09.69.4% of employeesb12.918.37.811.624.310.34.810.0Company financed R&D in US based on 1995 figures totalling $ 11.8 bnUS scientific and professional personnel totaling 34, 784 employeesSource: Pharmaceutical Research &am

6、p; Manufacturers of America, Industry Profile 19972003 data: C&EN 2003, 81 (50), 8.Ari KoskinenLaboratory of Organic Chemistry2021/7/238Market Exclusivity Times DecreaseAri KoskinenLaboratory of Organic Chemistry2021/7/239Development pipelineAri KoskinenLaboratory of Organic Chemistry2021/7/2310

7、Top 10 TherapiesDecember 6, 2004Volume 82, Number 49pp. 18-29Ari KoskinenLaboratory of Organic Chemistry2021/7/2311Top 10 ProductsDecember 6, 2004Volume 82, Number 49pp. 18-29Ari KoskinenLaboratory of Organic Chemistry2021/7/2312MergersDecember 6, 2004Volume 82, Number 49pp. 18-29Ari KoskinenLaborat

8、ory of Organic Chemistry2021/7/2313Off PatentDecember 6, 2004Volume 82, Number 49pp. 18-29Ari KoskinenLaboratory of Organic Chemistry2021/7/2314Patents expiringDecember 6, 2004Volume 82, Number 49pp. 18-29Ari KoskinenLaboratory of Organic Chemistry2021/7/2315Promising New DrugsDecember 6, 2004Volume

9、 82, Number 49pp. 18-29Ari KoskinenLaboratory of Organic Chemistry2021/7/2316Diversity of Drug Structures2021/7/2317BODFEHOO GNatural Products as Drug LeadsOMeMeOONHClHOOMeO MeA1Me OClO AOMeOHONO2MeO OCOMeMeOOOMeOHMe OMeOOOOH OHOHOGOOMeOOHO OOOOHOMeA2OHMeMeMeOHOOOHOHO OMeMeOMeEverninomicin 13,384-1M

10、eCallipeltoside AClinhibits proliferation of KB and P388 cellsprotects cells infected with HIVO16OHMeBr46OMe43OHOMe33OOHN 29OO24OO1NO9O5HOOHAOOMeB O H MeC DH OHEOOH HHN IMe H H O MeO HFMePhorboxazole AAzaspiracidcausative agent for 1995 human poisonings by contaminated Irish musselsMytilus edulisAri

11、 KoskinenLaboratory of Organic Chemistry2021/7/2318HHONOSO ONN H ONNHOH Me NHRCO N NMe S N CN NHHOONOOChemical Strategies in Drug DevelopmentIsolationStructure based synthesisHONRational Drug DesignOOMeHO O OHDesign based on Chemical DiversityMeCO2HClNN NONOHMorphine-Lactams(antibiotics)MeOOMe NMeSt

12、rychnineBrsplitTagamet Progesterone(anti-ulcer)MeOMeO OO OMeHQuinineValiumBr(tranquilizer)Ari KoskinenLaboratory of Organic Chemistry2021/7/2319High Throughput ScreeningPlants (500 000)Marine naturalproducts (106)Invertebrate naturalproducts (109)Compound librariesStructure baseddesignRecombinantmet

13、hodsPeptide librariesPeptidomimeticlibrariesAri KoskinenLaboratory of Organic Chemistry2021/7/2320Drug Development ParadigmsTraditional ApproachClinical/preclinicalObservationsDisease modelin vivoLEADin vivoStudies onpathophysiologyRational Approachin vitroDisease geneor in vivoValidated targetin vi

14、troLEADdesignTransgenic animalsAri KoskinenLaboratory of Organic Chemistry2021/7/2321Drug Development ParadigmsTARGET IDENTIFICATIONGeneralcombinatoriallibrariesLEAD GENERATIONBiasedcombinatoriallibrariesLEAD OPTIMIZATIONStructuralchemistryDRUG CANDIDATEAri KoskinenLaboratory of Organic Chemistry202

15、1/7/2322Chemical DiversityBasis set of 20Units203Library Entities8 000(e.g. natural amino acids)204160 000205Units3 200 000Library EntitiesThe number of different chemical entities,N = bx, where x = the number of steps,and b = number of different building blocks.Basis set of 100(e.g. carbohydrates)1

16、00310041005Units100031 Million100 Million10 BillionLibrary Entities1 BillionThe problem of combinatorial synthesisis not that of making compounds, butthat of finding ways to selectand identify the compounds:One must be able to extract the informationmade available by library screening.Basis set of 1

17、000(e.g. synthetic building blocks)10004100051 Trillion1 QuadrillionAri KoskinenLaboratory of Organic Chemistry2021/7/2323Combinatorial Chemistrysolid-phase organic chemistry (SPOC)combinatorial synthesisstructure elucidation based on deconvolution and taggingstructure-diversityautomationReviews:Spe

18、cial Issue: Acc. Chem. Res. 1996, 29, # 3 (March).Hermkens, P.H.H.; Ottenheijm, H.C.J.; Rees, D. Tetrahedron 1996, 52, 4527-4554.Frchtel, J.S.; Jung, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 17-42.Lowe, G. Chem. Soc. Rev. 1995, 24, 309.Ellman, J. Chemtracts: Organic Chemistry 1995, 8, 1-4.Pirrung,

19、M.C. Chemtracts: Organic Chemistry 1995, 8, 5-12.Czarnik, A.W. Chemtracts: Organic Chemistry 1995, 8, 13-18.Mitscher, L.A. Chemtracts: Organic Chemistry 1995, 8, 19-25.Dolle, R.E.; Nelson, K.H. J. Combinator. Chem. 1999, 1, 235-282.Ari KoskinenLaboratory of Organic Chemistry2021/7/2324198719891991 1

20、993199519971985Combinatorial Chemistry PublicationsCombinatorial Chemistry140012001000#800600400200PatentsPublications0YearAri KoskinenLaboratory of Organic Chemistry2021/7/2325Solid Phase Organic SynthesisPhPhOPhO OOOOO1. MeMgI2. H2O3. KOH4. H+PhMeOHCO2HAtrolactic acidKawana, M.; Emoto, S. Tetrahed

21、ron Lett. 1972, 4855-4858.OOScrambled product must arisethrough intraresin reactions.Intraresin reactions occur evenat resin loadings of 0.5 % (0.05CH2OC (CH2)5 C O CEt3*mmol/g resin!)OOOOO*Et3CO*Resin bound esterAutocleaved esterCrowley, J.I.; Rapoport, H. Accts. Chem. Res. 1976, 9, 135-144.Ari Kos

22、kinenLaboratory of Organic Chemistry2021/7/2326Combinatorial Library: Split Synthesis MethodPortioning-mixingFurka, A. et al. Int. J. Pept. Protein Res. 1991, 37, 487-493.Furka, A. et al. Bioorg. Med. Chem. Lett. 1993, 3, 413-418.Split SynthesisHruby, V.J. et al. Nature, 1991, 354, 82-84.Divide, Cou

23、ple and RecombineHoughten, R.A. et al Nature 1991, 354, 84-86.Ari KoskinenLaboratory of Organic Chemistry2021/7/2327aAbBcABConstruction of an Encoded Synthetic LibraryTags a, b, and c are attached to the samebeads as the growing oligomer chain. Theoverall structure of the hit oligomer can thenbe rea

24、d from the tag information.Dower, W.J. et al. PCT Appl. WO 93/06121.Needels, M.N. et al. PNAS 1993, 90, 10700.C Tags should have high information content, beamenble to high sensitivity detection anddecoding, and must be chemically orthogonal tothe oligomer protocol.C Single-stranded oligonucleotides

25、, coupled withPCR amplification: 8.2 x 105 synthetic peptides.abcalso: Lerner, R.; et al PCT Appl. WO 93/20242.Nielsen, J. et al. JACS 1993, 115, 9812-9813.POOLaAbBcCAAABACBABBBCCACBCCaaabacbabbbccacbccAri KoskinenLaboratory of Organic Chemistry2021/7/2328Spatially Addressable Parallel SynthesishMas

26、k 1XXXXXXXXAAXXNHNHNHNHDeprotectNH2NH2NHNHX-ANHNHNHNHCouplehMask 2XXEEFFAAXXXXXXCCDDNHNHNHNHX-BAABBRepeatAABBCoupleFodor, S.P.A.; Read, J.L.; Pirrung, M.C.; Stryer, L.; Yu, A.T.; Solas, D. Science 1991, 251, 767.Jacobs, J.W.; Fodor, S.P.A. Trends Biotechnol. 1994, 12, 19-26.Ari KoskinenLaboratory of

27、 Organic Chemistry2021/7/2329Spatially Addressable Chemical LibrariesFodor, S.P.A.; Read, J.L.; Pirrung, M.C.; Stryer, L.; Yu, A.T.; Solas, D. Science 1991, 251, 767.Jacobs, J.W.; Fodor, S.P.A. Trends Biotechnol. 1994, 12, 19-26.Pirrung, M.C.; Read, J.L.; Fodor, S.P.A.; Stryer, L. U.S. Pat 5,143,854

28、, 1992.Holmes, C.P.; Fodor, S.P.A. In Innovation and Perspectives in Solid Phase Synthesis and ComplementaryTechnologies; Epton, R., Ed., Intercept, UK, 1994.Ari KoskinenLaboratory of Organic Chemistry2021/7/2330Hydroxylamine ResinOHO NPhOPhOPhClNEt3/DMFPhO NOmax 1792 and 1743 cm-1N2H4/THFPhO NH2PhT

29、etrahedron Lett. 1997, 38, 7233-7236Ari KoskinenLaboratory of Organic Chemistry2021/7/2331Succinyl Amide LibraryOOPhPhO NH2OTHFPhPhO NHOOOHRNH2, DCC/HOBtDMF, rtHO NHOONHRHCO2H/THFPhPhO NHOONHRPhPhOOMeOOMeTetrahedron Lett. 1997, 38, 7233-7236Ari KoskinenLaboratory of Organic Chemistry2021/7/2332Pepti

30、dic and Peptidomimetic LibrariesOR1PhPhO NH2OO 10a, b, cHO NHOR1OHNR2+HO NHOR1OHNR2411Compound 10, 11, 1212entryR1 =aMePhbPhcBndPhR2 =OOMeOOMePhPhReagents and conditions: a) 60 C, 6 h, THF; b) (S)-phenylethylamine or amino acid eater hydrochloride/triethylamine, HOBt, DCC (5-fold excess), DMF, 6 h;

31、c) HCO2H/THF (1:3), 1 hScheme 3Tetrahedron Lett. 1997, 38, 7233-7236Ari KoskinenLaboratory of Organic Chemistry2021/7/2333Crude NMR8070HONHOOHNOOMe605040O30N OHO2010010987654321(ppm)Tetrahedron Lett. 1997, 38, 7233-7236Ari KoskinenLaboratory of Organic Chemistry2021/7/2334AnalysisMonitor conversion

32、on bead (e.g. Kaiser test forfree primary amines)Analysis of reaction products on beadAnalysis of combinatorial mixtures of productsAri KoskinenLaboratory of Organic Chemistry2021/7/2335IR on Bead1971: resin beads of chloromethyl polystyreneoxidation products in KBr disks (Frechet J.M. J.Am. Chem. S

33、oc. 1971, 93, 492-496.)FT-IR microspectroscopy: single bead from rxnto IR microscopy (Yan, R. J. Org. Chem. 1995, 60,5736-5738.Down to 100 pmoles of materialAri KoskinenLaboratory of Organic Chemistry2021/7/2336IR on BeadFT-IR can monitor progress of reactions:OOOOHOCOCl4O4NDiffuse reflectance infra

34、red Fourier transformspectroscopy (DRIFTS): fast, no samplepreparation (Chan, T.Y. Tetrahedron Lett. 1997,38, 2821-2824).Ari KoskinenLaboratory of Organic Chemistry2021/7/233713C:NMRlow abundance, usually large samplequantities, long pulsing19F, 31P used alsoMAS: nanoprobes allow for 10 mg resin (Sa

35、rkar,S.K. J. Am. Chem. Soc. 1996, 118, 2305-2306.)Ari KoskinenLaboratory of Organic Chemistry2021/7/2338Mass spectrometryMALDI-TOF MS: femtomole samples (Zambias,1994,TOF-SIMS (Brummel, C.L. Science 1994, 264, 399-402)CE-ESI MS (Dunayevskiy, Y.M. Proc. Natl. Acad.Sci. 1996, 93, 6152-6157)Ari Koskine

36、nLaboratory of Organic Chemistry2021/7/2339Is it feasible to make all possible interestingmolecules combinatorially?Only C,H,N,OAvg mol wt of permeable drugmolecule ca 500; max 750Avogadros number 6.1023Only one molecule each 10200moleculestotal mass: 10173 tonnesweight of Earth: 6.1021 tonnes!Weigh

37、t of the Universe: ca 1084500Mrtonnes!Ari KoskinenLaboratory of Organic Chemistry2021/7/2340Challenges in Combinatorial ChemistryDevelopment of diversity as a conceptDevelopment of solid phase synthesisDevelopment of fast, chemoselective, high yieldsolution synthesis methodsDevelopment of high speed

38、 analysisDevelopment of efficient screening strategies forminute amounts of compounds in mixturesAri KoskinenLaboratory of Organic Chemistry2021/7/2341Ari KoskinenLaboratory of Organic Chemistry2021/7/2342Ari KoskinenLaboratory of Organic Chemistry2021/7/2343More SourcesReviews:Dolle, R.E.; Kingsley

39、, N.K. J. Combin. Chem. 1999, 1, 235-282.Terrett, N.K. Combinatorial Chemistry OUP 1998, 186 pp.Thompson & Ellman Chem. Rev. 1996, 96, 555-600.Fruchtel & Jung Angew. Chem., Int. Ed. Engl. 1996, 35, 17-42.Asymmetric Catalysts:Liu & Ellman J. Org. Chem. 1995, 60, 7712-7713.Web:Tetrahedron

40、Information SystemMolecular Diversity: Diversity Lovers Forum; http:/ KoskinenLaboratory of Organic Chemistry2021/7/2344Target Oriented, Medicinal & Combinatorialand Diversity Oriented SynthesisSchreiber S.L.; Burke, M.D. Angew.Chem.Int.Ed. 2004 ,43 ,46 58Ari KoskinenLaboratory of Organic Chemis

41、try2021/7/2345Generating Skeletal DiversitySchreiber S.L.; Burke, M.D. Angew.Chem.Int.Ed. 2004 ,43 ,46 58Ari KoskinenLaboratory of Organic Chemistry2021/7/2346Small Molecule DiscoverySchreiber S.L.; Burke, M.D. Angew.Chem.Int.Ed. 2004 ,43 ,46 58Ari KoskinenLaboratory of Organic Chemistry2021/7/2347A

42、ri KoskinenLaboratory of Organic Chemistry2021/7/2348Complexity of Synthetic Targets This is where it started!2021/7/2349OErythromycin is.HOHOOOH ONMe2OHOOso hopelessly difficult that itsconquest cannot be conceived withinthe foreseeable future (Woodward,1956)O O OMeOAcErythromycin AAri KoskinenLabo

43、ratory of Organic Chemistry2021/7/2350Trends in Synthetic MethodologyPERIODTRENDOBJECTIVE/OUTPUT1950-1960Classical synthesis Target conquestHardwareof natural products Mechanisms, Spectroscopy1970-1980R.B. Woodward Nobel 1965for his outstandingachievements in theart of organic synthesisMultistep, st

44、rategyand transformationbased synthesisStereo/enantiocontrol SoftwareSynthetic methods1990-Designed molecules Selectivity, RecognitionFunction, Intelligence ContentE.J. Corey Nobel 1990for his development of the theoryand methodology of organic synthesisAri KoskinenLaboratory of Organic Chemistry202

45、1/7/23512021/7/2352Ari KoskinenBinding modelJ. Biol. Chem. 1997, 272, 23312-23316Laboratory of Organic Chemistry2021/7/2353Overlay of model & X-rayAri KoskinenLaboratory of Organic Chemistry2021/7/2354Calyculin analysisKoskinen, A.M.P.; Chen. J.Tetrahedron Lett. 1991, 32, 6977-6980.Pihko, P.M.;

46、Koskinen, A.M.P.Synlett 1999, 1966-1968.Pihko, P.M.; Koskinen, A.M.P.J. Org. Chem. 1998, 63, 92-98.2021/7/2355Spiroketal Model Studies2021/7/2356Spiroketal Model StudiesRauhala, V.; Nevalainen, M.; Koskinen, A.M.P. Tetrahedron 2004, 60, 9199.2021/7/2357Me3Al, THF/CH2ClSpiroketal Model StudiesO95 %OO

47、NBni) Et3N, Bu2BOTfii) 3-Benzyloxy-propionaldehydeTBSOOBn+ONOMeOTBSi) HNMe(OMe).HCl,1) BuLi, alkyne2) Weinreb amide 297% TBSOOBn O79 %ii) TBSOTf,ImH, CH2Cl2OONOBnBnOHOOBnOTBSOBn68%OBnOBn1) CSA, MeOH2) PhH, p-TsOH3) TEABnOOOBnOOOOO90 % (1:1)Aiguade, J.; Hao, J.; Forsyth, C. J. Org. Lett. 2001, 3, 979

48、-982Rauhala, V.; Nevalainen, M.; Koskinen, A.M.P. Tetrahedron 2004, 60, 9199.2021/7/2358C9-C19 FragmentKarisalmi, K.; Koskinen, A.M.P. Synthesis 2004, 1331-1341.2021/7/2359C9-C19 FragmentKarisalmi, K.; Koskinen, A.M.P. Synthesis 2004, 1331-1341.2021/7/2360Boron aldol TSsBernardi, A., Gennari, C., Go

49、odman, J. M. and Paterson I. Tetrahedron:Asymmetry 1995, 6, 2613.2021/7/2361C9-C19 FragmentC41O31C4C3C2C1O10C5O6C11C16C8C9C7C21C12C13C14C152021/7/2362C9-C19 Fragmentcrotylsilylation: Chemler, S. R.; Roush, W. R. J. Org. Chem. 2003, 68, 1319.Karisalmi, K.; Koskinen, A.M.P. Tetrahedron Lett. 2004, 45,

50、 8245.2021/7/2363Conclusions on I.A.I.5-ring induction usually more predictable than6-ringNatural products remain a rich source forchallengesInternal asymmetric induction often preferableto e.g. chiral catalysisAri KoskinenLaboratory of Organic Chemistry2021/7/2364R.L.Strausberg and S.L.Schreiber Sc

51、ience, 2003, 300, 294.Ari KoskinenLaboratory of Organic Chemistry2021/7/2365-TurnsSECONDARY STRUCTURAL MOTIFS OF GLOBULAR PROTEINSFeatures:4 residue turnsi i+3C=Oi to N-Hi+3Ari KoskinenLaboratory of Organic Chemistry2021/7/2366-Turn mimicsOUR GOALSynthesis of small peptides possessing a highpopulati

52、on of -turn structure in solutionHNPro-Gly MOTIFStrong turn inducer inpeptides and proteinsRNNOO H NOHORRRXaa-Pro-Gly-Xaa drawn in-turn conformationAri KoskinenLaboratory of Organic Chemistry2021/7/2367NH-Turn mimicsOUR GOALLocked conformation of the proline ringCOOHConformationallyconstrained pepti

53、demimicSide chain controlStructural study in solution (NMR)Elucidation of requirements for recongnitionand bindingNew class of DNA-cleaving agentsAri KoskinenLaboratory of Organic Chemistry2021/7/2368-Turn mimicsONPt/CBoc80%ON1CHOBocCOOMePh3P2CH2Cl2ON3COOMeBocE/Z 96:472%DIBALTol, -50oCON4Boc88%OHH2H

54、2, Raney NiMeOH5aONBoc5bOHPPh3, CX4ONBocX6a X=ClAcOH80%HOXNHBoc7a X=Cl 48% (from 5b)1) PhCOCl, Py2) Recryst.Hex/Et2Otrans/cis 86:1495%6b X=Br 90%1) 1N HCl,7b X=Br 91%JonesBzOXKHMDS100oCONHBoc8a X=Cl8b X=BrTHF, 0oC71%NBoc9OBz2) dioxane,10% Na2CO3,Fmoc-ClNFmoc10acetoneOH59%96%NFmocCOOH11Nevalainen, M.

55、 J. Org. Chem. 2001, 66, 2061-2066.Ari KoskinenLaboratory of Organic Chemistry2021/7/2369Prolines in TurnsArg-Val-Asp-Val3Ala Leu Gly AlaAla ProGly AlacAla MP Gly AlatAla MP Gly AlaMP =NVal-Asp-Val-Arg3OKrische, M.J.Ari KoskinenLaboratory of Organic Chemistry2021/7/2370Synthesis of TetrapeptidesAlaX

56、GlyAlaCbzOHH2NOtBuCbzOHH2NOMeCbzCbzOtBuOHCbzH2NOMeOMeX = Leu, Pro, 4-MeProCbzCbzOMeNHMeKrische, M.J.Ari KoskinenLaboratory of Organic Chemistry2021/7/2371-Proline ConformationsFigure 4dx4HOCHNx1CCx2x3C HHOCHNCCC HRamachandran ARamachandran Bx1: 0 - -30 x2: +15 - +50 x3: -15 - -30 x4: +5 - +25x1:x2:x3:x4:+20-30+20-5+35-40