Plants as a Source of Drugs

1
Plants as a Source of Drugs

• Ralph N. Blomster Ph. D.
• Professor Emeritus
• Department of Pharmaceutical Sciences
• School of Pharmacy
• University of Maryland, Baltimore

2
Emergence of Proprietary Products

• Plants have been used for centuries for treatment
  of disease. Used in home preparations.
• British brands of patent medicines were imported
  during colonial days and US developed our own
  brands.
• Groups of itinerant sales people (Hucksters)
  traveled across country selling Nostrums that
  they quite often made in the back of their wagons.

3

• Many had fanciful names i..e. Swamp Root and
  Snake Root Elixirs, Chief Powotans Elixir and
  Lydia Pinkham Vegetable Compound and contained
  mixtures of plants.
• The sales of these continued, along with
  outrageous claims, until the Pure Food and Drug
  Act of 1906.

4

• Around this point in time many drug companies
  were developed to provide pre-made, standardized
  products of plant materials freeing the
  pharmacist from the onerous need to prepare many
  of their stock solutions. This allowed for
  standardized products to be readably available.

5
(No Transcript)
6
Isolation and Modification of Plant Compounds

• For centuries, Willow Bark (Salix species) was
  used for the treatment of arthritis, fever,
  various aches and pains.
• German chemists isolated a simple glycoside from
  the plant which they called salicin.
• It was a prodrug. It broke down to salicylic acid
  which was active but was kerolytic (destroyed
  tissue. We then modified it to prevent bleeding.

7
(No Transcript)
8
(No Transcript)
9
What did we learn?

• We found a non-steroidal anti-inflammatory
  analgesic and antipyretic.
• We found a flat configuration to allow a fit on a
  flat receptor site or an enzyme. It is acidic and
  strongly ionized at physiological pH.
• Aqueous solubility to concentrate in plasma and
  some lipid solubility to penetrate biological
  membranes.

10
From using a plant extract that had
pharmacological activity

• We isolated a chemical that had the activity.
• We were able to use that chemical as a molecular
  model to produce coumpounds with similar action
  and fewer side effects.
• We could use the compound to relate to and define
  its structure activity relationship

11
On occasion the active compound is developed in
the plant by accident

• Medacago sativa is used as a silage plant.
• A Wisconsin dairy farmer found his cows dying
  from internal hemorrhages.
• Chemical investigation showed that a simple
  coumarin moiety had dimerized and was the culprit
• Changes in the structure led to anti-coagulants
  that were safer and less toxic.

12
(No Transcript)
13
(No Transcript)
14
(No Transcript)
15
Digitalis purpurea

• Introduced by Wm. Withering as a therapeutic
  agent for the treatment for dropsy (congestive
  heart failure)
• Active constituent is a cardiac glycoside
• It is a steroid that has a highly specific and
  powerful action on cardiac muscle.
• Increases the force of systolic contraction,
  myocardium recovers as a result of increased
  cardiac output and circulation. Heart rate is
  decreased through a reflux vagal effect. Improved
  circulation tends to improve renal secretion and
  relieves edema

16
Structural needs

• An alpha. Beta unsaturated lactone ring
• A 17 beta side chain
• Glycoside formation at the 3-position of the
  steroid nucleus. The sugar portion confers
  solubility properties which is important in
  absorption and distribution, also influences
  binding site on receptor. Oxygen substitution on
  steroid influence distribution and metabolism.
  More hydroxyls more rapid onset and dissipation.
• Agycone has cardiac activity

17
Digitoxigenin
18
Cinchona succirubra

• Contains quinoline alkaloids, two major ones are
  quinine and quinidine.
• Has unusual quinuclidine ring
• Quinine used to treat malaria and as a skeletal
  muscle relaxant in nocturnal leg cramps.
• Quinidine to treat cardiac arrhythmias
• Overdoses lead to temporary loss of hearing,
  impaired sight, tinnitis
• Replaced by synthetic hydroxyquinolines

19
(No Transcript)
20
(No Transcript)
21
Atropa belladonna
22
Datura strammonium
23
Solanaceous Plants

• Also known as the Deadly Nightshade Family.
• Atropa belladonna
• Datura stramonium
• Mandragora officinalis
• Tomato and potato
• Have been used as poisons and hallucinogens
  (witches and sorcerers)

24
(No Transcript)
25
Atropine and Scopolamine

• Atropine is an antispasmodic,antisialagogue, to
  reduce respiratory secrertions in anesthia,
  gastric secretions in ulcers, and nasal sinuses
  in colds. Antidote for cholinesterase poisoning
  (physostigmine and organophosphate insecticides)
• Scopolamine has a depressant activity on the
  central nervous system used for motion sickness
  and preanesthetic sedation.
• Overdose rxns, skin rash, skin flushing, mouth
  dryness, eye pain, pupil dilation, blurred
  vision, light sensitivity, difficulty in urination

26
Claviceps purpurea
27
Claviceps purpurea

• Causes a fungal infection of rye called Ergot.
  St.Anthonys Fire
• It produces a wide variety of alkaloids the most
  important of which are ergonovine, ergotamine and
  a mixture of ergocristine ergokryptine, and
  ergocornine marketed as ergotoxine.
• Produced both from the plant and in saprophytic
  culture.
• Ergonovine is water soluble and ergotamine and
  ergotoxine are water insoluble (they are called
  peptide alkaloids)
• Ergonovine is oxytocic in all dosage forms is
  much more rapid than with the other two.
• Ergotamine has oxytocic properties but is used
  for treatment of vascular headaches and cluster
  headaches- migraines.

28
(No Transcript)
29
Colchicum autumnale
30
Cholcicum autumnale

• Called Autum Crocus
• Produces an alkaloid called colchicine a mitotic
  poison that is used in the treatment of
  gout.Mechanism of action not known.
• It is an anti-mitoticand causes the chromosomes
  of the cell wall to divide with out the formation
  of spindle fibers and subsequent cell division to
  form daughter cells. ie. Polyploidy.
• Showed anti-tumor activity.

31
(No Transcript)
32
(No Transcript)
33
(No Transcript)
34
(No Transcript)
35
Papaver somniferum

• The opium poppy. Produces opium which is a
  mixture of alkaloids known as opium alkaloids the
  chief of which are morphine, codeine and
  papaverine.
• The alkaloids act at several sites in the CNS to
  produce analgesia.
• Are agonists at the mu and kappa receptor
  subtypes.
• Mu receptor responsible for analgesia, euphoria,
  respiratory depression and physical dependence.
• Activity at Kappa receptor responsible for
  analgesic activity at spinal level, miosis and
  sedation.

36
Most common centrally acting analgesics share
certain common structural features.

• 1. Central quaternary carbon.
• 2. A phenyl group or isostere attached to
  this carbon

• 3. A tertiary nitrogen

• 4. A 2 carbon bridge separating the tertiary
  nitrogen and the central carbon.

37
(No Transcript)
38
(No Transcript)
39
(No Transcript)
40
Erythroxylon coca
41
Erythroxylon coca

• Cocaine has multiple central and peripheral
  nervous system actions.
• A psychomotor stimulant over most of its
  effective dose range it has a strong abuse
  potential.
• Acts by prolongation of dopamine in the synapse
  by blocking the dopamine reuptake mechanism.
• Local anesthetic by otolarangolists and eye
  surgeons
• Model for a large number of local anesthetics

42
(No Transcript)
43
Cola nitida
44
Cola nitida

• Contains purine bases (methyl xanthines)
• Are central nervous system stimulantsin varying
  degrees
• Caffeine (1,3,7-trimetylxanthine) diuretic and
  CNS stimulant
• Theophilline (1,3-dimethylxanthine)
• Smooth muscle relaxant and diuretic some CNS
• Theobromine (3,7-dimethylxanthine) Smooth
  muscle relaxant, diuretic and little CNS
  stimulation

45
(No Transcript)
46
(No Transcript)
47
(No Transcript)
48
(No Transcript)
49
Catharanthus roseus

• In studying this plant for activity as an oral
  hypoglycemic it was found to produce peripheral
  granulocytopenia and bone marrow depression in
  rats. They isolated vinblastine which produced
  severe leukopenia in rats.
• Svoboda saw anticancer potential and from the
  dozens of alkaloids isolated 4 bisindoles which
  had activity vinblastine, vincristine,
  vinleurosine and vinrosidine.
• It takes500 Kg of catharanthus to yield 1 gm
  vincristine.
• Similar to colchocine they arrest cell division
  at metaphase. Bound tightly to tubulin and
  interfer with the microtubule system, Inhibits
  polymerization of tubulin into microtubules

50
(No Transcript)
51
(No Transcript)
52
Taxus brevifolia
53
Taxus brevifolia

• Produces taxol or paclitaxel.
• Took 20,000 lbs of bark to yield 1 Kg of the
  dirterpenoid and 1 lb was needed to treat 100
  patients.
• Unique MOA, enhances polymerization of tubulin
  and induces the formation of stable,
  non-functional microtubules.
• Used in treatment of metastatic carcinoma of the
  ovary and in treatment of breast cancer, after
  treatment failure.

54
(No Transcript)
55

• There is a problem of limited supply of bark, the
  complex structure which precludes commercial
  synthesis.
• Needed a renewable source. Used leaves of
  Japanese Yew an ornamental which produced the
  terpene moiety Braccatin III which could then be
  used to semisynthetically produce taxol

56
(No Transcript)
57
Other Antitumor Plant Compounds

• Camptothecin from Camptotheca accuminat. A
  quinoline
• Showed unacceptable mylosuppression (too toxic)
• Interest revived when it was found to act by
  selective inhibition of topoisomerase I (involved
  in cleavage and reassembly of DNA) Made molecular
  changes to the structure to provide Topotecan,
  Irinotecan.
• The Camptothecins and taxanes provide about one
  third of the global market.

58

• Podophyllum peltatum (May apple)
• Podopyllotoxin found in the resin is anti-tumor
  but too toxic, so developed epipodophyllotoxins
  i.e Etoposide and teniposide.
• Binds tubulin causing DNA strand break during G-2
  phase of the cell cycle by inhibiting DNA
  topoisomerase II

59
Steroid Production

• In the early 1930s they discovered structure and
  activity of steroids, the only source was from
  animal organs.
• In 1934 it took 625 Kg of ovaries from 50,000
  sows to yield 20 mg. progesterone. 80 per gram.
• Russell Marker, working with steroid like
  compounds in plants, had the idea that he could
  make progesterone from plant sterols. Went to
  Mexico and developed a degradation technique to
  produce progesterone from steroidal saponins in
  plants. Diosgenin from Dioscorea species was his
  starting material. He prodiuced 3 Kg.

60

• The Upjohn Company found that a mold could
  convert progesterone to the 11- hydroxy compound
  which led the way to the fermentation processes
  to produce the major steroids

61
(No Transcript)
62
(No Transcript)
63
(No Transcript)
64
(No Transcript)
65
11 hydroxyprogesterone
66
(No Transcript)
67
(No Transcript)
68
Genetic Engineering Pharmacobiotechnology

• Recombinant DNA technology.
• Vaccines
• Production of plant compounds that are difficult
  to isolate or synthesize.
• Protein engineering.
• Receptor studies.

69
The role of compounds from natural sources in
medicine

• Provide a number of extremely useful drugs that
  are difficult, if not impossible to produce
  commercially by synthesis
• Provide basic compounds that may be modified to
  be more effective or less toxic
• Prototypes or models for synthetic drugs with
  physiological activity.
• Precursors of drugs that are difficult to
  synthesize de novo

70
Examples of Recently Introduced Natural Product
Drugs

• Artemisinin from Artemisia annua used in
  traditional Chinese medicine
• Galantamine isolated from Galanthus sp and
  Narcissus sp. Treatment of Alzheimers
• Calanolide A from Calophyllum lanigerum Anti-HIV
• Hyperizine from Hyperizia serrata improve
  cognative functions Alzheimers, dementia.