Introduction

• There is documentation from 4000 years ago that plants have been used to treat diseases

• In the US, 25% of all prescription drugs are from plants or based on plant-derived compounds.

  • 50% if fungal compounds are included

• Herbal Medicine is still very big in many parts of the world.

  • There’s an Amazonian Conservation team working with indigenous people in Suriname to identify their herbal plants and protect them from habitat destruction and global warming.

    • Preserves the knowledge.

Prescription and Over The Counter (OTC) drugs

• All our plant-based prescription drugs started out as herbal remedies somewhere.

The sequence of events for drug discoveries

1. Knowledge that the plant has healing properties

   1. in literature or word of mouth

2. Isolation and structural characterization of the active component(s).

3. Mode of Action

4. Clinical Trials

5. Drug Development

Plant Secondary Metabolites

• Phenolics

  • Aspirin and related NSAIDs

• Terpenoids

  • eg. steroid

• Alkaloid

  • Contains Nitrogen

  • Are usually basic (alkaline) and taste bitter

  • Pronouced actions on the nervous system

  • quinine, caffeine, nicotine, cocaine, ephedrine

Digitalis Purpurea (Foxglove)

• Active components were found to be steroid-type compounds

  • affects Na+K+ATPase

  • A diuretic

• Used to treat Congestive Heart Failure

  • Does not cure the disease, just treats the symptoms

• Digitoxin is the prescription drug

  • individualized doses

History

• William Withering was an English Clergyman that studied a herbal tea that was used to treat “dropsy”

  • It contained 20 plants

  • He found that the active principle was foxglove

• Dropsy is a condition characterized by severe bloating due to fluid accumulation

  • AKA Congestive Heart Failure

Aspirin

• 80 million aspirin tablets are taken every day in the US

• Aspirin doesn’t come from a willow tree or occur naturally

History

• 2500 years ago the Greeks used an infusion from white willow (Salix Alba) bark to treat rheumatism, fever, and pain

  • Many Native American tribes had independently discovered the healing powers of willow bark

• 1839: Salicin was identified in willow bark extracts by German chemists

  • Aromatic ring with a sugar group

• Salicylic acid (SA) was synthesized in labs in Germany to treat gout and rheumatism

  • Salicin is converted to SA in the stomach naturally (the aromatic ring loses the sugar group)

  • Other plants contain SA too including Spirea and wintergreen

• Acetyl Salicylic acid was more palatable and had fewer side effects

  • Acetyl Salicylic acid is what aspirin actually is

So now we got Aspirin

• Aspirin is an analgesic (pain-killer), antipyretic (fever breaker), and anti-inflammatory

• Aspirin is easy to make in a laboratory, its cheap, and effective

Mode of Action (how it works)

• British Biochemist, John Vane showed that aspirin inhibits prostaglandin synthesis (1970)

• Arachidonate acid (the precursor of prostaglandins) is synthesized in mammals from linoleic acid (18:2)

• Prostaglandin: considered to be a “local hormone,” stimulates inflammation, regulates blood flow

  • Made on site

• Prostaglandin synthase has 2 different catalytic activities, one is cyclooxygenase (COX) activity.

  • Aspirin irreversibly inhibits COX activity which is how it decreases inflammation, pain, and fever

    • Arachidonate cannot bind in the groove to get converted to a Prostaglandins

Using Aspirin as a Prototype for Designing Other Drugs

• Other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

  • Like Ibuprofen and Naproxen

• Thousands of compounds have been synthesized in the lab, based on aspirin as a prototype

• The use of aspirin for pain and inflammation has been, to a certain extent, superseded by other NSAIDs

  • NSAIDs are more gentle on the stomach

• Because aspirin inhibits COX activity it inhibits the biosynthesis of thromboxanes (later in the prostaglandin pathways)

  • Thromboxanes are used in blood clotting

  • This is the basis for the effect of aspirin in preventing blood clots (thrombi)

  • Aspirin is taken daily by millions of people to reduce blood clots, heart attacks, and stroke

  • Salicylic Acid is known to have some positive health effects

    • in fact, aspirin is metabolized in the human body into Salicyclic acid very quickly (within a minute)

Drugs for Parasitic Diseases

• 3 billion people get parasitic diseases a year

Malaria

• Malaria comes from the Italians’ belief that it was caused by “Bad Air”

• The worse of these is Malaria which affects millions a year

• Estimated there are half a billion clinical cases of Malaria a year

• Usually confined to tropical/subtropical regions

• Plasmodium: is the causative organism (protest) of malaria

  • 4 species are responsible for most of the cases

  • Plasmodium is transmitted from person to person by a mosquito vector

• Life Cycle of a Plasmodium

  1. When a female, Anopheles mosquito, harboring the malaria parasite in her salivary glands, bites an individual, the sporozoite stage of the parasite is injected. The sporozoites are carried to the liver in the bloodstream

  2. In the liver, merozoites are produced and released into the bloodstream

  3. The merozoites invade RBCs and multiply

  4. After a period of time the RBCs rupture, releasing a new generation of merozoites, which then infect other RBCs. The cycle is synchronous with the simultaneous rupture of RBCs and release of merozoites and toxins, causing the periodic fever and chills

  5. Male and female gametocytes are formed in some RBCs. If the gametocytes are ingested when an Anopheles mosquito bites an infected individual, they can complete sexual reproduction and begin the infection cycle anew.

Cinchona

• Cinchona: contains quinine for the treatment of malaria

  • Make tea with the bark

  • Also called the fever bark tree

• Thought to have been used 1st in Peru

  • Documented use in the early 1600s

• Knowledge of the tree and samples of the bark was taken to Europe by Jesuit missionaries in the 17th century, then we went worldwide.

• The active ingredient was 1st isolated by French scientists in 1820

• 1880: the 1st determination that malaria was a parasitic disease

• 1896: confirmed transmission of the parasite by a mosquito to human

• 1944: the 1st synthetic version (Chloroquine) is made

  • The occupation of Java during WWII by the Japanese shut down the major supplier by quinine to the world

• Quinine and chloroquine both block the life cycle of the Plasmodium at the red blood cell stage

Other Synthetic forms

• Chloroquine - used extensively

  • less toxic and more effective than Quinine

• Primaquine

• Mefloquine and many more

• There are some problems associated with Plasmodium developing resistance to quinine and its derivative

  • So other plants are being studied

Artemisia Annus (sweet wormwood)

• Artemisia Annus contains Artemisinin which is a sesquiterpenoid lactone, with an endo-peroxide bridge

• Fewer side effects than the quinines

• Kills the parasite in the RBC stage, but not the Liver stage so cannot be taken as a prophylactic

• Artemisia is a Chinese plant that is grown in controlled growth rooms

• The World Health Organization recommends using artemisinin in quinine-resistant malaria areas

• However, the 1st case of resistance has been confirmed near the Thailand/Laos Border

• The search for more plants/drugs continues

Other Ways of Treating Malaria

• You can run mosquito control

  • insecticide

  • bed nets

  • decreasing the amount of standing water

• Vaccines are also in the works.

Plants for Treating Cancer

Catharanthus Roseus (Vinca rosa) → Rosy Periwinkle

• The active components of the Catharanthus are the Vinca Alkaloids.

• The whole plant is used.

History

• 1950: Canadian Scientists received a sample of Vinca leaves from Jamaica, which was thought to be useful for treating diabetes.

  • They tested extracts of the plant on lab rats

  • The rats were all dead in 3 days

  • They had all died of bacterial and fungal diseases

  • Analysis of the dead rats showed low WBC counts

• 1961: the FDA approves the use of Vinblastine

• 1963: the FDA approves the use of Vincristine

Clinical Uses

• Used in the treatment of leukemias and other cancers of the lymphatic system

• The two main alkaloids are Vinblastine (VLB) and Vincristine (VCR)

• In the plant, Vinblastine is probably formed first and vincristine is formed later as an oxidized product

  • VLB has a methyl group (CH3) while VCR has an aldehyde group (CHO) instead

• Vinblastine: used in combination with other drugs to treat generalized Hodgkin’s disease, and various lymphomas

• Vincristine: used to treat acute lymphocytic diseases, and used in combination with other drugs to treat Hodgkin’s disease, lymphosarcoma, etc.

Satisfying the Demand

• The yield of the vinca alkaloids is 0.0002% from the leaves

  • VCR is more biologically active but found in smaller quantities

• To satisfy the demand, the plant is collected from natural sources and cultivated sources in Madagascar, Australia, South Africa, South America, West Indies, India, and the Southern US.

• It takes over 500 kg of Vinca leaves to get 1 g of VCR

Mode of Action

• Vinblastine and Vincristine block mitosis

  • They prevent the polymerization of the tubulin so that cells go into metaphase arrest

Taxol (Taxus Brevifolia) → Pacific Yew

• Taxol is now known as Paclitaxel

  • Only found in the bark

• Taxus translates to yew

  • A member of the gymnosperm phylum and the Taxaceae family

• The Pacific yew has no cones but fleshy “berries” (still NOT a fruit but an aril)

History

• 1958: the National Cancer Institute commissioned USDA (United States Department of Agriculture) Botanists to collect samples from 30,000 plants

• 1962: Extracts from bark, twigs, and needles of the Pacific yew were tested

• 1963: Extracts of bark showed biological activity (it slowed the growth of cancer cells in culture)

• 1971: The chemical structure of a complex diterpene was determines

  • C47H51NO14 → molecular weight 854 g

• 1979: the mode of action was shown to be different from that of the Vinca Alkaloids

• 1983: National Cancer Institute commenced phase 1 trials, although taxol was in very short supply

• 1994 (April): The FDA approves use for metastatic breast cancer that has recruited within 6 months of initial chemotherapy

• 1994: Two groups simultaneously publish the total synthesis of taxol

Mode of Action

• Taxol promoted the polymerization of microtubules but prevents depolymerization (so no daughter cells are formed)

Clinical Uses

• Initially used to treat cancer patients who were terminal

  • Some showed no further growth of ovarian tumors, and some tumors even shrunk.

• Taxol is particularly effective against solid tumors

• Metastatic breast cancer that has recruited within 6 months of initial chemotherapy

Supply and Demand

• Since taxol was in short supply during the phase 1 trials, further research was delayed.

  • Difficulties in getting enough taxol for experimental use

  • Only found in the bark and removing the bark kills the tree

• It took six 100-year-old trees to get enough taxol to treat one person

• This reinforced the desperate need for alternative sources of taxol

• Taxol has 11 stereocenters in the molecule so technically 2048 stereoisomers could exist

  • Making it from scratch in the Lab is too difficult to be profitable

  • Maybe we can find a similar compound in related species

    • The European Yew had a compound that contained the complicated ring structure in the needles.

    • We can work off the ring from the European Yew and try to convert it to Taxol

• Taxol was BMS’s strongest performer in 1995 with 62% sales increase over the previous year

• In 2000 annual sales reached $1.6 billion

Advantages of the European Yew

• The European Yew has a less restrictive growing range

• The needles can be harvested repeatedly without killing the tree

• It is much easier to do semi-synthesis than the total synthesis

Dietary Supplements

• Many of these come from plants

• These are called “Botanicals” or “Herbal”

• These are not regulated the same way as drugs or foods.

  • The Food and Drug Administration (FDA) in the US regulates food and drugs but does not regulate the production of dietary supplements

• You can’t actually make claims, just suggestions

  • St. John’s Wort: used for treating mild depression, (mood enhancer)

  • Echinacea: used for “healthy immune function”

• Sometimes problems can arise because dietary supplements have not been tested properly

  • The FDA will then issue a warning

  • In extreme cases, they will remove a product from the market

Ephedra

• Ephedra is the source of the alkaloid ephedrine

  • Ephedrine was 1st identified in 1887 and added to modern prescription drugs during the 1920s

  • Decongestant effects due to relaxation of bronchial muscles, CNS stimulant that acts similar to adrenaline

• When taken in excess they give the same effects as the illegal drug “ecstasy”

• In excess, it causes heart attack, strokes, seizures

• It was banned in the US in 2004

  • Supplement companies quickly tried to get this overturned, taking the case all the way to the supreme court.

    • They were unsuccessful

• This is also one reason allergy medication is now sold over the counter

  • It contains pseudoephedrine which has the same effects as ephedrine

    • With fewer stimulation effects

    • In addition, it is an ingredient for making illegal methamphetamines