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					Natural Products
   Approximately 25% of Rx drugs are plant natural
    products or are semi-synthetics

   Approximately 15% of all Rx drugs are based on
    compounds initially isolated from plants

   Greater than 50% of the OTC products on the market
    contain at least one component of plant origin
Common plant-derived drugs
   Morphine: isolated from Papaver somniferum

   Narcotic Analgesic

                              NCH3




                          O
                  HO               OH
Common plant-derived drugs
   Quinine: isolated from Cinchona officialis.

   Antimalarial
                                            H


                                H       N
                           HO       S
                                R
                   CH3O

                                N
Common plant-derived drugs
   Vinblastine: isolated from Cantharanthus roseus

   Anticancer                              OH
                                        N

                              N
                              H        CO2CH3
                       CH3O


                        H 3C N

                     CH3O2C       OH    N

                      CH3CO2
Common plant-derived drugs
   Atropine: isolated from Atropa Belladonna

   Anticholenergic agents

                H3C
                      N
                              H   OH

                          O

                              O
Common plant-derived drugs
   Digitoxin: from Digitalis purpurea (foxglove)

   Cardiac glycoside: CHF
                                                 O
                                                      O

                                                      H

                                             H

                  H3C                    H       OH
                        O
                HO (
                            )O       H
                            3
                  HO

                  D-Digitoxoside
Common plant-derived drugs
   Taxol: isolated from Taxus (Pacific Yew)

   Anti-cancer
                                      O       OH
                      OH
                  H
                  N
                                                    H
              O        O                  H        O
                             OH               O
                                  O
                                          O
                                      O
Common plant-derived drugs
   Etoposide: isolated from Podophyllum Peltatum

   Anti-cancer                   O
                          O
                   H 3C   O
                           O      O
                            H     H O

                                               O

                                           O


                            MeO            OMe
                                      OH
Common plant-derived drugs
   Colchicine: isolated from Colchicum Autamnale

   Gout                          O

             MeO                  N
                                  H
              MeO

                                   O
                               OMe
Common plant-derived drugs
   Acetyl Salicylic Acid: isolated from Salix Alba

   Analgesic

                                CO2H

                                O

                            O
Natural Products Chemistry
Primary metabolites

  1. Direct function in primary biochemical pathways
       are essential for life (G-3P, R-5P)


Secondary metabolites

  1. Synthesized directly from primary metabolites

  2. NOT involved in the primary life-sustaining processes
       important in proper biochemistry
Secondary Metabolites
Primary classes
 Terpenes – Cholesterol synthesis

 Phenylpropanoids – Fatty acids

 Polyketides – Fatty acids

 Steroids – Progesterone, etc.

 Glycosides – Protein glycolosys, etc.

 Alkaloids – Amine containing moiety
Terpenes
Common examples and plant parts:
 Cinnamon –in bark



   Peppermint – in “hairs” on leaves

   Lemon - in the rind

   Rose – in the petals

   Ginger – in the rhizome
Terpene Synthesis
Synthesized by the mevalonic acid pathway
            Acetic acid           HMG (hydroxymethylglutaric acid)
                 O
                                             H3C     OH
       3
           H3C       OH                   HO2C         CO2H

                                        HMG-CoA
                                        Reductase

 Mevalonic acid 5-pyrophosphate              Mevalonic acid

  H3C       OH                                H3C    OH
                   O   O          ATP
HO2C               P   P                  HO2C
                 O   O   OH                               OH
                   O   O
                   H   H
Terpene Synthesis cont.

                                  Mevalonic acid 5 -pyrophosphate
                                   H3C      OH
                                                   O   O
                             HO2C                  P   P
      IPP synthase                               O   O   OH
                                                   O   O
      -CO2 and H2O                                 H   H


                               IPP
               O   O        isomerase                  O   O
               P   P                                   P   P
             O   O   OH                              O   O   OH
               O   O                                   O   O
               H   H                                   H   H
Isopentenyl pyrophosphate (IPP)          Dimethylallylpyrophosphate (DMAP)
IPP and DMAP Biological “Isoprene” Building blocks:
C10 Geranyl isoprenoid synthesis

                DMAP                 IPP


                     OPP     +             OPP
                                     H

        - pyrophosphate     Geranyl pyrophosphate
              (-OPP)        synthethase (GPP-ase)




                                   OPP

               Geranyl pyrophosphate (GPP)
IPP and GPP Biological “Isoprene” Building blocks:
 C15 Farnesyl isoprenoid synthesis



                            OPP      +                OPP
                                                H
       Geranyl pyrophosphate (GPP)              IPP


          - pyrophosphate       Farnesyl pyrophosphate
                (-OPP)          synthethase (FPP-ase)



                                          OPP

               Farnesyl pyrophosphate (FPP)
FPP Biological “Isoprene” Building blocks:
 C30 Squalene synthesis

                        2
                                                      OPP
  Squalene                  Farnesyl pyrophosphate (FPP)
  Synthase




             Squalene                           Cholesterol
                              HO
Mevalonic Acid Pathway Produces Cholesterol
                                                           H3C
                                                                 O
                   OH                                  H3C
               H3C  H                                            H

               H                             H3C       H

           H       H                               H       H
  HO                                     O
       Estradiol                              Progesterone
                                     OH
                                 H3C   H
                       H3C       H

                             H       H
                   O
                       Testosterone
Mevalonic Acid Pathway Produces Cholesterol




                              CO2H                         OH
               H3C
           HO H3C         H                                 O
                                           O       H3C      OH
        H3C       H
                                         H3C       H
              H       H
  HO                                           H       H
          H                          O
       Deoxycholic Acid                   Cortisone
        (A Bile Acid)
Terpene Classes
   C5 – Hemiterpenes
   C10 – Monoterpenes
   C15 – Sesquiterpenes
   C20 – Diterpenes
   C25 – Sesterterpenes
   C30 – Triterpenes
   C40 – Carotenoids
Examples of Terpenes

                                      O
             OH



     C10 - Menthol          C10 - Camphor




               C40 - Carotene
Phenylpropanoids
   Occur as mixtures with Terpenes in essential oils
    isolated from plants
       Flavonoids – water soluble plant pigments

       Anthocyanidins – improve microcirculation & nightvision

       Coumarins - Anticoagulants

       Lignans – Anti-cancer drugs

       Tannins – in green tea, red raspberry & witch hazel
           Interact with Theophylline/Aminophylline (bronchodilators)
Phenylpropanoid synthesis
Shikimic Acid Pathway

   Phosphenolpyruvate
        CO2H
          OP                    CO2H              CO2H
        CH2                       O                 OH
                                CH2               CH
         +                 HO                HO
        CHO                       OH               OH
           OH                     OH               OH
           OH                     OP               OP
           OP
   Erythrose-4-phosphate         "Arabino" 7-phosphate
Shikimic Acid Pathway


       CO2H                                CO2H
              HO       CO2H
         OH
       CH
  HO          O           OH           O        OH
                                -H20
        OH           OH                    OH
        OH
                  5-Dehydro-           5-Dehydro
        OP        quinic Acid          shikimic acid
Shikimic Acid Pathway


     CO2H              CO2H             CO2H



 O         OH     HO        OH     PO        OH
     OH                OH               OH
  5-Dehydro
  shikimic acid    Shikimic acid    5-Phospho-
                                    Shikimic acid
Shikimic Acid Pathway
Phosphenolpyruvate
       CO2H
         OP                     O                        O
       CH2                          CO2H                     CO2H
        +               HO2C
                 -H2O                      -H2O
       CO2H
                                           -CO2
                               OH
                                                  Phenyl-
  PO        OH                                    pyruvic Acid
                        Prephenic Acid
       OH
Shikimic Acid Pathway

        O                                NH2
                          NH2
            CO2H                            CO2H
                            CO2H



                                       OH
 Phenyl-
 pyruvic Acid      L-Phenylalanine   L-Tyrosine
Shikimic Acid Natural Products
         CH2                                CH3




            Eugenol       Anethole
CH3O
       OH                              OMe

               CHO
                              CO2CH3
                                  OH



       Cinnamaldehyde   Methyl Salicylate
Shikimic Acid Flavones
                           OH

 HO        O                         HO        O



       OH O                                OH O
                                                          OH
      A Flavone                           An Isoflavone


                                     OH
                       +
           HO          O
                                     An Anthocyanidin
                                OH
                  OH
Shikimic Acid Coumarin Products



       O      O                          HO       O    O

   Coumarin                    O         7-Hydroxycoumarin
                                         "Umbelliferone"
                     ONa           CH3



                     O     O

                  Warfarin Sodium
Shikimic Acid Lignins
            HO2C         OH                               OH
                                     Catechol
 Gallic Acid
                         OH                               OH
                    OH                          OH
                                                     OH
             OH
 O                            HO         O
                                                     OH
                    O
  O                                                       OH
                                              OH
                    O
                                    OH        O
                                   HO
      MeO          OMe                             OH
             OH                          OH
  Podophyllotoxin                      Procyanidin B-1
    (A Lignan)                      A synthetic Lignan
                                    (a condensed Tannin)
Shikimic Acid Tanins
Polyketide Biosynthesis
Highly modified via cyclization, reduction and oxidation
                O                         O       O       O       O       O

   10     H3C       OH                                                        NH2

   Linear polymerized                 O                                   SCoA
                                              O       O       O       O
       Acetate

  OH      O HO H O          O             OH      OH OH OH O
               O
                                NH2                                           NH2
                     OH                                                   OH
           OH
  Cl     CH3     N                                CH3
             H3C   CH3
       Chlorotetracycline                     6-Methylpretetramide
Glycosides: Aglycone plus a Sugar
                            O
                                    O                       H3C
                                                       HO           O
                                          +                             OH
                 HO H3C             H              3
                                                           HO
              H3C       H                                   D-Digitoxose

                    H       OH                         O
       HO                                                    O
               H
    Digoxigenin - an Aglycone
                                              HO H3C            H
                                         H3C       H
                    H3C                        H       OH
               HO (             O                                 Digoxin
                                    )O    H
                    HO              3
An Aglycone is the non-sugar compound that remains after replacement of a
glycosyl group in a glycoside
Alkaloids
• All contain at least one nitrogen atom
• Names often end in “ine”, Large complex structures
Alkaloids - Examples
• All contain at least one nitrogen atom
• Names often end in “ine”, Large complex structures
                                       H3C
                                                  CO2CH3
                                         N
                           N
                                                      O
                           CH3
               N
                                                  H       O

          Nicotine - a Pyridine          Cocaine - a Tropane
                                                          N
                     O     CH3
           H3C             N
                 N
                             N                    N
             O       N
                     CH3                      O          O
            Caffeine - a Purine           Strychnine - Indole


        Others: Quinine - a quinoline, Morphine - a Isoquinoline
What should I remember?
   Many drugs are derived from plants
   Primary v. Secondary metabolites
   Key secondary metabolites
     Terpenes

     Phenylpropanoids
     Polyketides

     Steroids

     Glycosides
     Alkaloids

   Reactions that they undergo
     Mevalonic acid pathway
     Shikimic acid pathway

   Products that are formed
     Endogenous (i.e. steroid hormones, etc.)

     Exogenous (drugs)

				
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posted:9/23/2011
language:English
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