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Chapter 10
Manipulating Molecules and
Designing Drugs
Is our society becoming
dependent on prescription drugs?
How harmful are illicit drugs?
Herbal remedies: Is “natural” safer than synthetic?
How are effective drugs designed?
A wonder drug?
The classic white willow tree, Salix alba, provides more
than just shade and shelter for nature’s animals.
Salicin is the key ingredient that is isolated from the
tree and converted into one of our most reliable and
heavily used drugs, aspirin!
It is used as an antipyretic-fever reduction.
White willow tree
It is used as an analgesic-pain
reliever, and as
an anti-inflammatory agent.
salicin
10.1
Semi-synthesis of aspirin: from natural
product to marketed drug
Salicylic
acid
White willow tree
acetic acid
anhydride
Possible side effects:
1. Heartburn
2. Nausea
3. Reye’s Syndrom
4. Ringing in ears
5. Rash, itch
6. Shortness of breath
acetylsalicylic acid
(aspirin)
acetic acid
Would this drug make it
through FDA scrutiny today?
10.1
Organic Chemistry –
The Study of Carbon Compounds
There are over 12 million known organic compounds.
Why carbon? Carbon has the remarkable ability to bond
in multiple ways:
10.2
Some different ways to represent molecular structures:
CH3CH2CH2CH3
Ball-and-stick formula
Structural formula
Space-filling model
CH3CH(CH3)CH3
n-butane and isobutane are isomers, molecules that have the same chemical
formula, but with different structures and properties
10.2
Representing molecular structures with line-angle drawings:
H
H
H
C
H
H
H
H
C
C
C
C
H
C
H
=
H
H
H
H
H
iso hexane, or 2-methyl pentane
H
H
H
H
C
H
H
C
C
Each vertex (or end of a line) represents
a carbon with an appropriate number of
hydrogen atoms.
C
H
C
=
H
H
H
cyclopentane
10.2
10.2
Representations of benzene (C6H6), an important
part of many drug molecules.
10.2
Functional groups - arrangements of groups of atoms which
impart characteristic physical and chemical properties.
10.3
More Important Functional groups
The presence and orientation of functional groups are responsible for the action
of all drugs. See Chapter 9 for more info on functional groups.
10.3
Ester Formation
O
This OH and this H form H2O
C
O
C
O
OH
OH
H
H
O
C
O
CH 3
O
O
+
H
OH
C
CH 3
this O attaches here
Ester functional groups are often found in drugs,
flavorings, and fragrances.
10.3
What are the functional groups in the aspirin molecule?
1. Benzene ring
2. Carboxylic acid
3. Ester
10.3
Examples of polar molecules
Functional groups may impart a polar aspect to a
molecule.
A polar molecule has partial charge separation.
d- = “partial negative” d+ = “partial positive”
10.3
Salt Formation
OH CH3 CH3
OH CH3 CH3
CH CH
NH
Pseudoephedrine
freebase
+
H
Cl
CH CH
NH2Cl
Pseudoephedrine
hydrochloride
The salt forms are often preferred as drugs because of:
• Increased water solubility
• No odor
• Higher melting points (longer shelf life)
10.3
Hormones, our chemical messengers, are produced by the body’s
endocrine glands.
Hormones encompass a wide range of
functions and a similarly wide range of
chemical composition and structure.
Enzymes are proteins that act as
biochemical catalysts, influencing
the rates of chemical reactions.
Aspirin works by inhibiting the production of certain enzymes
responsible for producing specific hormones.
10.4
Aspirin and other drugs that are physiologically active, but not
antiinfectious agents, are almost always involved in altering the
chemical communication system of the body.
Aspirin, as well as other non-steroidal antiinflammatory (NSAID)
drugs, work by inhibiting the catalytic activity of certain enzymes.
The mode of action is due to the ability of aspirin to block the action
of cyclooxygenase (COX-1 and COX-2) enzymes from producing
the hormonal compounds called prostaglandins.
Certain prostaglandins are responsible for the body’s response to
pain, inflammation, and fever.
10.4
Prostaglandins cause a variety of effects. They produce fever and
swelling, increase sensitivity of pain receptors, inhibit blood vessel
dilation, regulate the production of acid and mucus in the stomach,
and assist kidney functions.
By preventing COX-2 enzymes from catalyzing prostaglandin
production, aspirin reduces fever and swelling. It also suppresses
pain receptors and so functions as a painkiller.
But the drug (as do other NSAIDs) also inhibit COX-1 enzymes
that primarily make hormones that maintain proper kidney
function and keep the stomach lining intact.
Thus, NSAIDs drugs are not sufficiently selective to affect COX2 without shutting down COX-1 as well.
10.4
Researchers raced to create nearly a dozen new candidate drugs that
block COX-2 alone. This work resulted in the emergence of a new
class of medicines in the late 1990s called COX-2 inhibitors.
Two wildly popular and heavily prescribed COX-2 inhibitors are
Vioxx and Celebrex. These new “superaspirins” were touted as
being safer and more effective than currently available NSAIDs.
The premise is that since they do not act on the COX-1 enzymes,
there should be fewer gastrointestinal (GI) side effects.
The reality is that they have not been proven to be more effective or
safer than aspirin or ibuprofen. In fact, they have been proven to be
more dangerous than helpful.
Use the Web to write a short essay on the life and death of “super
aspirins.”
10.4
Two COX-2
Inhibitors
Uncertain future for the COX-2 inhibitors is due to emerging
evidence of their questionable safety. As of 2008, they have been
pulled off the shelf by their manufacturers.
10.4
Aspirin, revisited – mode of action
COX enzymes
Prostaglandin production
COX -1: liver function, stomach lining
COX-2: fever, pain sensation,
inflammation
10.4
Drug Discovery-serendipity
Sir Alexander Fleming, British
bacteriologist
Working with Staphylococcus-a
bacteria.
A colleague working in same
building was working with
Penicillium notatum-a fungus
that produces penicillin.
Actual photo of petri dish Flemming showing
inhibition of growth of bacteria where penicillin
landed on the dish.
Series of chance occurrences,
and penicillin was discovered.
10.5
Drug Discovery-serendipity
H
O
S
N
PhOCH2
N
O
Penicillin V
“In the fields of observation, chance favors
only the prepared mind”
-Louis Pasteur
CH3
CH3
COOH
How many functional groups
can you identify in the structure
above?
10.5
Drugs may be broadly classified as:
aspirin
1. Those that cause a physiological
response in the body.
anticancer drugs
morphine
2. Those that kill foreign invading
organisms.
antibiotics
antifungal agents
10.5
Drug interactions at the cellular level
The lock and key model.
A substrate is a substance whose reactions
are catalyzed by an enzyme. Here you see
a drug occupying the receptor site of the natural
substrate.
10.5
The functional groups and their placement in three-dimensional
space determines to a large degree a molecule’s biological activity.
The portion of a molecule that determines the biological
effects of a drug is called the pharmacophore.
10.5
Combinatorial Chemistry
Combinatorial chemistry is the systematic creation of large numbers of small
molecules in “libraries” that can be rapidly screened in vitro for potential new
drugs.
The benefits of using combinatorial chemistry:
1. Many molecules can be created at a rapid rate.
2. The cost of the procedure is much cheaper than traditional molecule synthesis.
3. Large libraries of bioactive lead compounds can be produced relatively inexpensively.
10.5
Chiral molecules have 4 different groups
attached to a central atom.
A chiral molecule and its nonsuperimposable mirror image are a special
kind of isomer called enantiomers.
Enantiomers have identical physical
properties.
The only way we can tell them apart is by
seeing their effect on plane polarized light.
10.6
However, the body can tell them apart. These two
enantiomers may have very different actions in the human
body.
One enantiomer fits into a receptor site, while the other does not. The
molecule on the right will have (possibly) no affect on the human body.
10.6
Consider the two enantiomers above.
Dextromethorphan is a safe cough suppressant.
Levomethorphan is an addictive opiate.
10.6
Steroids perform many functions in the body:
C
A
D
This is the basic carbon
skeleton for all steroids.
B
10.7
Functional groups in some common steroids
alcohols
carboxylic acid
ketones
Can you identify
the functional
groups
in the other
examples?
10.7
Prescription, Generic, and Over-the-Counter
Medicines
A generic drug is chemically equivalent to the pioneer drug, but cannot be
marketed until the patent protection on the pioneer drug has run out after 20
years.
The lower priced drug is commonly marketed under its generic name, in this
case alprazolam instead of Xanax.
10.8
St. John’s Wort
10.9
Ephedra – used safely for thousands of years as herbal remedy
known as Ma Huang.
In 2003, several deaths related to the ingredients led the FDA
(in 2004) to ban ephedra products. At this time, there are
ongoing discussions to make the product available again.
10.9
Ephedra
The herb contains the amphetamine-like
alkaloids – ephedrine and the less active
pseudoephedrine.
Pseudoephedrine is used as a decongestant
Ephedrine is a bronchodilator (opens the airways), and a stimulant
10.9
Drugs of Abuse
10.10
Marijuana – Cannabis sativa
THC, or delta-9-tetrahydrocannabinol is the active drug in
marijuana.
Medical uses continue to be argued, the Federal Government is
opposed.
10.10
OxyContin contains oxycodone
Oxycodone has been used
safely for many years.
But this formulation includes a time-released mechanism for long-lasting
treatment of chronic pain.
Drug abusers quickly determined how to get around the time-release and
were able to rapidly ingest large amounts of oxycodone. The effects were
said to be similar to heroin.
Over-prescribed in the Appalachian areas in late 1990s and early 2000s.
Many became addicted.
10.10