Advances In Natural Product Chemistry: Benefits Of .

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7/25/2013International Center Webinar SeriesFree webinar – July 31, 2013 at 2:00PM ESTwww.acs.org/icWorking abroad has many benefits Work alongside scientists from across the globeGrow professionally and personallyGain a global perspectiveBrush up on your foreign language skillsExperience a different cultureEnhance your resume!Featuring speakers from the European Commission’sEURAXESS, an initiative brought forth to provide information andsupport to researchers wishing to pursue their research careers inEurope. The webinar will feature a presentation on the currentEuropean research landscape and international trends, as well ashighlighted exchange programs.3 If you enjoy ACS Webinars every Thursday please support the program!www.join.acs.orgACS Network (search for group acswebinars)www.communities.acs.orgFind the many benefits of ACS membership!42

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7/25/2013 Upcoming ACS Webinarswww.acswebinars.orgThursday, August 1, 2013Alternative Careers:Chemistry and the Art DetectiveDr. Suzanne Lomax, Organic Chemist, National Gallery of ArtPatricia Simpson, Director of Academic Advising, University of IllinoisThursday, August 8, 2013Writing Winning Proposals Heilmeier CatechismCelia Elliott, University of Illinois at Urbana-ChampaignDr. Dave Harwell, Assistant Director, ACS CareersContact ACS Webinars at acswebinars@acs.org9 Advances in Natural Product Chemistry:Benefits of Evidence-Based Chinese MedicineDr. Bill CourtneyChef/ChemistCHEESE-OLOGYDr. Chun-Tao CheProfessor of PharmacognosyUniversity of Illinois at ChicagoSlides available now! Presentation available ONE WEEK after the tact ACS Webinars at acswebinars@acs.org105

7/25/2013ACS Webinar - July 25, 2013Advances in Natural Products Chemistry –Benefits of Evidence-Based Chinese MedicineChun-Tao CheNorman R. Farnsworth Professor of PharmacognosyDepartment of Medicinal Chemistry and PharmacognosyandWHO Collaborating Center for Traditional MedicineCollege of Pharmacy, University of Illinois at ChicagoChicago, Illinois 60612, U.S.A.Question 1Do you use any herbal or traditional medicinalproducts?o Yes, regularlyo Yes, but only if recommended by people I trusto Yes, but only if I have read study reportso Never6

7/25/2013Natural Drugs Natural (non-synthetic) Crude (undergone only simplepreparation procedures) Complex chemical compositionVS(the “metabolome” ) Variable in quantities Many structures unknown Possibly 1 active ingredient Unclear pharmacological mechanism May act on multiple targets( systems biology) Possible synergism / antagonismNatural Products Chemistry Isolation / purification of secondary metabolites Structural elucidation and characterization of secondarymetabolites (spectroscopic properties, stereochemistry, etc.) Structural modification Chemical synthesis Biosynthesis and microbial transformationAnalytical ChemistrySeparation ScienceSpectroscopySynthetic Organic ChemistryBiotechnologyNew Drug Discovery7

7/25/2013Focus of this talk Quality and standardization of herbalmedicines Multi-target concept of herbalmedicines Synergy research on herbal medicinesContributions of Natural Products Chemistryto Herbal Medicine Understanding the chemical composition Identification of active principles Rationalizing the traditional useUncaria rhynchophyllaXian et al., E-CAM, 2012, 802625.Rhynchophylline IsorhynchophyllineSetting analytical standards for quality controland assessment8

7/25/2013Intens.x10 6R2OROOO4 R Glu9 R H38R1OHOOHOOMeO12576R1 OH; R2 GluR1 H; R2 GluR1 OH; R2 HR1 R 2 HOMeOMeOHRO6Xyl-OO3 R Glu8 R HO-Glc21OMeO4Astragalus RootOMe7526489001020304050Time [min]Contributions of Natural Products Chemistryto Herbal Medicine Understanding the chemical composition Identification of active principles Rationalizing the traditional use Setting analytical standards for quality controland assessment Detection of toxic components9

7/25/2013Sim et al., Molecules, 18: 5235-5250, 2013Aristolochic acidJapanesestar aniseAnisatinChinesestar aniseShen et al., J. Chromatogr. A, 1259: 179-186, 2012.Question 2What do you think is the biggest issue that wouldmake people skeptical about the use of herbalproducts?O UnreliablequalityO UnsafeO UnprovenO Oftenefficacynot recommended by doctorsO Peoplehave little knowledge about herbal products10

7/25/2013Herbal ProductESFAFFIECTAYCYQUALITYModified from Bauer, Drug Info J, 32, 101–110, 1998Standardization Current practice Quantitative measurement of small number of markercompounds (often with little biological irrelevance to theclinical effects) Chromatographic profile (TLC / HPLC fingerprints) basedon small number of reference peaks (or bands) More appropriate to assess the whole medicine inthe context of multiple components Plant metabolomics analysis provides betteranalytical methods for standardizing herbalmedicines11

7/25/2013The Metabolomic Approach A holistic, simultaneous and systematic qualitative andquantitative determination of plant metabolites Dealing with the distribution of metabolites in itsentirety (metabolome) Allowing quick and efficient identification andquantification of secondary metabolites in a mixture A breakthrough to accelerating and streamlining theanalytical process of medicinal plant research Easily coupled to bioactivity screening data Making use of analytical processes such asspectroscopy, chromatography, and multivariateanalysisApplications of Metabolomicsin Medicinal Plant Research Classification of medicinal plants Species and varieties Geographical origin Adulterants Quality control and standardization Characterization of plant cell cultures Proof of efficacy of medicinal plants fromurine and/or blood samples12

7/25/2013A Workflow illustrating the plant metabolomic strategyfor herb identificationGao et al., J Chromatogr A, 1245: 109-116, 2012.LC-QTOF MS and PCA-SVM Analysis ofseven Lonicera (honeysuckle) speciesflower budsLonicera confusaL. dasystylaL. fulvotomentosaL. hypoglaucaL. japonicaL. macranthoidesL. similesGao et al., J Chromatogr A, 1245: 109-116, 2012.13

7/25/2013Principal component analyses of four Glycyrrhiza species derived fromnegative ionization mode LC–MS data (m/z 100–1000). (A) Score Plot (B) Loadingplot for PC1 contributing mass peaks and their assignments: 8 liquiritin apioside;12 neolicuroside; 31 glycyrrhizin; 37 glycycoumarin; 26 yunganoside G1;27, yunganoside G2.Farag et al., Phytochemistry, 76: 60-72, 2012.1H NMR peak based principal component analyses of differentGlycyrrhiza samples. (A) Score Plot. Group discrimination is related toqualitative and quantitative differences in the saponin and flavonoid patterns.(B) Loading plot for PC1 components: 1 glycyrrhizin; 2 sucrose; 5 liquiritigenin;6 isoliquiritgenin; 7 4-hydroxyphenyl acetic acid; 10 rhamnose moiety.Farag et al., Phytochemistry, 76: 60-72, 2012.14

7/25/2013Applications of Metabolomicsin Medicinal Plant Research Classification of medicinal plants Species and varieties Geographical origin Adulterants Quality control and standardization Characterization of plant cell cultures Proof of efficacy of medicinal plants fromurine and/or blood samplesIntegrative andComprehensiveQuality AnalysisTreatmentBiological ResponsesSample preparationMetabolomic AnalysisNMR-basedmeasurementGenomic ResponseTranscriptomic ResponseProteomic ResponseMetabolomic ResponseLCMS-basedmeasurementChemical Fingerprint Biological FingerprintMultivariate Data Analysis(e.g. PCA, HCA, ICA, PLS, PLS DA, OPLS DA)15

7/25/2013DAD1 D, Sig 230,8 Ref off (IBS\IBSFOR 1\C1-T.D)mAULC-MS Fingerprint of a Chinese medicine formulafor Irritable Bowel Syndrome studies8006004002000020406080100120minIp et al., Chinese Medicine, 5:8, 2010.APCI MS Data (Positive Ion)Peak IdentificationM/QMOther Peaks1 Esculin2 Chlorogenic acid3 Aesculetin4 Paeoniflorin5 prim-O-Glucosylcimifugin6 Magnoflorine7 Liquiritin8 5-O-Methylvisamminoside9 Hesperidin10 Columbamine11 Jatrorrhizine12 Epiberberine13 Coptisine14 Palmatine15 Berberine16 Glycyrrhizic acid17 Schisandrin18 Honokiol19 Magnolol20 Schisandrin A341 (M H) 179355 (M H) 163179 (M H) 498 (M H2O) 301, 179469 (M H) 342 (M) 419 (M H) 307, 257453 (M H) 291610 (M) 465, 449, 303338 (M) 338 (M) 336 (M) 320 (M) 352 (M) 336 (M) 823 (M H) 647, 471, 453, 406433 (M H) 415266 (M) 263266 (M) 261417 (M H) MS2 of M/QMIP179163134, 123, 109301, 179307297, 265290463323, 294323, 294304, 292337, 308321, 292402, 347, 31616

7/25/2013vehiclehonokiolmagnololschisandrin Aschisandrin Bsaikosaponin 4.5-4.0Concentrations of markers (logM)200###150#100**********50************* ***0tr1234567891011121314151617181920100% of 5-HT-induced contraction125C%of acetycholine-inducedcontractionIn vitro activities of component herbs and chemical ingredients on intestinal contractilityconcentration at 100 MApplications of Metabolomicsin Medicinal Plant Research Classification of medicinal plants Species and varieties Geographical origin Adulterants Quality control and standardization Characterization of plant cell cultures Proof of efficacy of medicinal plants fromurine and/or blood samples17

7/25/2013Question 3What do you believe is more effective?OMixture of herbal ingredients in a natural or semipurified formOMixture of conventional drug with herbal drugOPure chemical compoundTherapeutic ApproachesReductionistic Approach Mainstream approach One target – one drug Selective ligand (singlesubstance) acts on a singledisease target Aiming for highly specificand safe drugs Not quite effective fordiseases of multi-factorialpathogenesis Subject to development ofresistanceHolistic Perspective Many diseases possess multicausal etiology and a complexpathophysiology Multi-drug therapy Most traditional medicinalsystems make use ofcombination of herbs Mixture of compounds (multicomponent) act on multitargets Network Pharmacology wouldhelp explain the mechanismsof multi-component herbalmedicines18

7/25/2013Tao et al., J. Ethnopharmacol. 145: 1-10, 2013.Synergy Effect The efficacy of herbal medicines may be a result of thecombined action of multiple constituents. Studies have shown the therapeutic superiority of herbaldrugs as compared with single constituents. The practice of Chinese medicine is built upon the conceptof synergistic or polyvalent effects among various plantmetabolites present within the herbal decoction. The specific components responsible for these effects, andthe fundamental mechanisms by which they interact, haverarely been demonstrated. A synergy-directed fractionation approach was developedto probe into the possible mode of synergy.19