Transcript Cyclooxygenase (depicted above) inhibited by Salicylic Acid

Salicylic Acid
• Is recorded written history as far back as 1500 B.C. Egyptian Physician
Papyrus 500 B.C. by the Greek doctor Hippocrates.
• This remedy was also among the ancient Sumer, Lebanon, Assyria as well as
the Cherokee and other Native Americans.
• End of the 19th century was regularly prescribed as pain reliever, however it
wasn’t synthesized or purified until 1838 (by Johann Pina).
• The bark extract is called salicin (Latin for white willow) for which it gets its
name. However, it had the nasty side effect of causing serious bleeding and
ulcers in the stomach.
• Later synthesized by Kolbe (1859) from phenol: same synthesis used today!
From Salicin Extract to Aspirin
Plant sources:
Willow
myrtle
American teaberry
Meadowsweet
O
OH
3
Carboxylation
(Kolbe's method)
HO
CO2, 125 oC, 100 atm
Na O
Salicylic acid
Acetylation
Ac2O, reflux
Extraction
1
2
Sugar
Saligenin
Oxidation
(in the body
or in lab)
OH
HO
O
HO
OH
OH
Salicin
O
OH
O
OH
O
4
Hydrolysis
HO
(in the body
or in lab)
2
O
acetylsalicylic acid
(Aspirin)
Saligenin
1. Extraction has been going on for thousands of years, however, the first person
credited with isolating Salin was Johann Buchner in 1828.
2. Raffaella Pina was first to synthesize by hydrolyzing Salicin to remove sugar unit,
then oxidizing to obtain Salicylic acid (the same process that occurs in the body).
3. Kolbe found a more convenient and inexpensive route through treating phenolate
with CO2 at elevated temperature and pressure.
4. Felix Hoffmann discovered a useful route of converting Salicylic acid into Aspirin.
Bioproduction
O
CO2
P
O
+
Phosphoenolpyruvate
or PEP (Product of
glycolysis)
H
CHOH
CHOH
CH2 O P
Shikimate
Pathway
4 steps
H2O
Erythrose-4-Phosphate NADPH
(Product of Pentose
Phosphate Pathway)
HO
2xP
H2O
NADP+
Shikimate
Pathway(2)
3 steps
CO2
CO2
OH
OH
Shikimate
ATP
PEP
2xP
ADP
OH
Isochrismate
Synthase
and
CO2
OH Salicylate
Synthase
Chorismate
(almost aromatic)
• Produced by the willow tree and concentrated in the bark, also found
in many nuts, fruits, veggies and herbs.
• Serves as a hormone in many plants and it believed to control: plant
growth and development, photosynthesis, transpiration, ion uptake
and transport.
• It’s also believed to be involved in endogenous signaling, mediating
in plant defense against bacteria and fungi.
• It can be methylated by the plant at the alcohol to form methyl
salycilate, which is volatile and can signal to other plants around.
• Believed to be derived from the amino acid phenylalanine.
OH
Chorismate: A Useful Intermediate for
Plants and Microbes
3 common amino acids
Certain bacteria rely on phenozine dyes to produce colors
N
N
Phenazine
N
N
NH2
N
Example of Red Phenozine Dye
Industrial Production
OH
CO2Na
ONa
CO2
HCl
CO2H
OH
NaOH
Mechanism:
:OH
O C O
OH
NaOH
O:
H
CO2
O
CO2
O
pKa 10
Salicylic acid reaction chamber
• Originally extracted from willow bark, but this took a lot of effort and
would take many trees to make metric tons.
• Now it’s made from phenol using a Kolbe-Schmidt reaction (120 oC
with 100 atm CO2, named after Kolbe efforts in industrializing this
process).
• It’s estimated that 50 million pounds produced each year.
Common Uses
Common modern day uses:
1. Production of Aspirin
2. Used for skin treatments in shampoos – causes skin to
shed leading to uses such as: treatment of acne, dandruff
prevention, and removal or calluses, corns, and warts.
3. Muscle ailment gels (i.e. icy-hot) that absorb through the
skin.
Effects in the Body
• Inhibit the activity of
Cyclooxygenase in the body.
• This prevents Prostaglandins
from being produced this inhibiting pain.
• Unfortunately, it taste terrible and causes
severe irritation of the mucosal
membrane in digestive tracks leading to
ulcers.
Cyclooxygenase (depicted above) inhibited by Salicylic Acid
Modifications and Analogous Drugs
HO
CO2H
OH
O
+
Salicylic Acid
O
O
Acetic Anhydride
O
N
H
Acetaminophen
CO2H
O
O
Acetylsalicylic Acid
(Aspirin)
HO2C
HO2C
Naproxen
OCH3
Ibuprofen
• Salicylic Acid can be converted to Acetylsalicylic Acid (Aspirin) using a reaction
with acetic anhydride.
• First produced by Charles Frederic unknowingly made it in 1853 but didn’t
purify it and could confirm the structure. It was purposefully made by Felix
Hoffmann in 1897 who tried making a less irritating medicine for his arthritic
father.
• Two years later Bayer & Co marketed it as Aspirin.
• It has all the advantages of Salicylic Acid without the stomach problems and
works even better!
• Later other Aspirin analogs were produced giving medications like
Acetaminophen (Tylenol), Ibuprofen (Advil), and Naproxen (Aleve) which are
gentler on the stomach.
Problems with Aspirin
and other COX inhibitors
Crystal structure
representation of COX-1
Crystal structure
representation of COX-2
• More forms of COX exist – for example COX-1 and COX-2.
• Inhibiting COX-1 leads to ulcers and other problems in
the stomach, COX-2 prevents pain.
• Salicylic Acid, Aspirin, Ibuprofin and etc inhibit both …
for this reason prolonged use leads to ulcers.
Celebrex and Vioxx – Specific COX-2
Specific Inhibitor
Vioxx
• Overuse of Aspirin, Acetaminophen, Ibuprofen, and Naproxen leads
to ulcers.
• This is a problem with patients who need to take pain killers over a
long period of time.
• For this reason a COX-2 specific pain killers were synthesized to avoid
stomach problems by both Merck (Vioxx) and Pfizer (Celebrex).
• The downside – it’s more expensive to make and deleterious side
effects: Vioxx was completely removed from the market after high
incidents of heart attacks and strokes (over 18 months of use).
Bicarbonate
• The ancient Egyptians used natron, a mixture consisting
mostly of sodium carbonate and sodium bicarbonate as a
cleansing agent like soap.
• In 1791, a French chemist, Nicolas Leblanc was first to make
Sodium Bicarbonate unknown that it is “organic” in the sense
of containing the element carbon.
• In 1846 two New York bakers, John Dwight and Austin Church,
established the first factory using Leblanc’s method.
Bioproduction
• Produced by water and CO2 gas in the body to first produce
carbonic acid, then is deprotonated to produce Bicarbonate.
• This process is catalyzed by an enzyme called Carbonic
Anhydrase which speeds up the process of combining CO2 and
water.
• Carbonic Anhydrase has a zinc atom in its active site that
helps catalyze the reaction.
Common Uses of Bicarbonate
1. Cooking (Baking Soda) – Quick breads, makes veggies softer
and removes acids (including citric acid).
2. Industrial Neutralization of acids and bases.
3. Medical Uses: Used to treat heartburn, add needed cations
(i.e. K+ or Ca+) quickly to blood and for allergic reactions
(poison oak/ivy, bee sting, ect.) among other treatments.
4. Used in tooth pastes and deodorants.
5. Used in cleaning supplies and detergents.
Possibly Used in Worms?
2 minute image acquisition
Tetrafluorofluorescein
(pKa = 3.7)
Intestinal lumen
acid
base
Fluorescent
Non-fluorescent
Aaron Bender, Zach Woydziak, Jessica
Sand, and Jennifer Heppert
Buffering the pH in Organisms
• Keeps the pH of blood and other fluids in organism around 7.4
(pKa carbonic acid 6.3).
• Too high of pH will lead to congestive heart failure, too low
and your body experience acidosis.
• Bicarbonate is ultimately the vehicle to which CO2 goes from
your cells to your mouth.