Drug Design and

Isomerism
 Drug Action
• The effectiveness of a drug is often
related to the chemical structure and
polarity of the substance.
• Factors that affect how a drug reacts
include:
1. Chirality
2. Geometrical isomerism
3. Ring strain
4. Polarity

2
 What is chirality?
• Isomers
• Stereoisomers
• Diastereomers
• Enantiomers
• Racemates
 Enantiomers
- Identical chemical and physical properties in symmetric
environments
- Except rotation of plane-polarized light
- A mixture of equal parts of an isomer and its enantiomer is
racemic
 Importance For Drug
Design
• The body is chiral
• Enantiomers of compounds can
react differently in the body, with
greatly helpful or harmful
outcomes
“Nature has a way of knowing how to make things work.
Reactions often run in a catalytic mode, and material use, energy,
and waste are minimized. Many molecules are chiral, and their
unique handedness has both intricate and dramatic influences on
how they interact with biological systems.”
 Chirality Affects Drug Behavior
• The presence of an asymmetric or chiral
carbon atom in a molecule resultsin two
different optical isomers or enantiomers.
• Two different enantiomers can behave in
very different ways in the body.
• The most famous example of this difference
was found in with thalidomide.

7
 Thalidomide
• German drugmaker Chemie Grünenthal introduced thalidomide, under
the name Contergan, to the German market on Oct. 1, 1957
• It was a sedative to treat insomnia as well as to reduce nausea associated
with pregnancy.
• By 1960, the drug was in more than 20 countries in Europe and Africa.
• On Nov. 18, 1961, the German paper Welt am Sonntag reported on a
study finding that pregnant women who had been taking thalidomide
were giving birth to babies with gross deformities.
• "By November 27, Grünenthal had pulled the drug off the market,
blaming the sensationalism of the press"
 Thalidomide
• Thalidomide has two
optical isomers, one of Chiral
Carbon
which is a tranquilizer
while the other is a
powerful teratogen.

• Originally used to treat

morning sickness
during pregnancy.
The high incidence of fetal deformities
• Now used to treat has led to increased diligence in
some symptoms of approving drugs for use.
Hansen’s disease When new drugs are developed now
(Leprosy). The pharmacological activity of each
optical isomer must be studied
separately. 9
 Thalidomide and Leprosy
Thalidomide is used in the
treatment of Erythema nodosum
leprosum (ENL), a painful
inflammatory dermatologic
reaction of leprosy

10
 Geometric Isomers Differ in
Behavior
• Geometric isomerism occurs in both organic and
inorganic compounds.
• Diaminechloroplatnium (II) is an inorganic complex
that as been used to treat certain types of ovarian
and testicular cancers.
• Diaminechloroplatnium (II) exists in both cis and
trans isomers.

11
 Cis and Transplatin
The structures of the cis and trans forms
are shown below:

Cis-platin is an effective anticancer drug, while

Trans-platin is not effective at all.

12
Cisplatin as an Anti-cancer Drug
• Cisplatin can diffuse through
a cancer cell membrane.
• In the cell it exchanges a
chloride ion for a water
molecule forming a complex
ion.
• This complex ion binds to
the cancer cell DNA
preventing it from replicating
correctly.

The cis-platin form is just the

right size to bind to the guanine
bases on the DNA. 13
 1938 Federal Food,
Drug & Cosmetic Act

• required proof of safety to be submitted

to FDA before a drug could be approved
for marketing
• did not require demonstration of efficacy
• allowed "experimental" use of drugs while
approval was being sought, which meant
that a drug could be distributed widely
before it was approved
 Thalidomide sparked major changes for the
FDA

”’the drug approval process was under considerable criticism, particularly the
quality of the scientific data submitted in New Drug Applications and the lack
of an efficacy requirement,’ according to Kelsey, writing in the 1996 annual
report of FDA's Office of Compliance. ‘The nature and magnitude of the
thalidomide disaster,’ she wrote, spurred the swift passage of legislation
addressing the shortcomings of the 1938 law that had been sitting in Congress
before the disaster. Known as Kefauver-Harris Drug Amendments, they were
signed into law by President John F. Kennedy in October 1962.”
 Impact on Today
• Today it is often easier to submit
single enantiomeric chiral drugs
rather than racemic chiral drugs
• Old racemates are often
reassessed as single enantiomers
• Synthesis, separation and analysis
of chiral compounds has advanced
greatly, and is highly sought
 Potential advantages of
single enantiomer products
• Less complex, more selective
pharmacodynamic profile
• Potential for an improved therapeutic
index
• Less complex pharmacokinetic profile
• Reduced potential for complex drug
interactions
• Less complex relationship between
plasma concentration and effect
 Some differences:
• “the mean daily dose … was reduced by approximately one third
compared to the racemate”

• “the cardiotoxicity of the drug appears to be predominantly

associated with the (R)-enantiomer”

• “significantly reduced negative inotropic effect (approximately

half) was observed with the single enantiomer compared to the
mixture”

• “between 130 and 160 fold more potent than the (R)-
enantiomer”

• “faster onset of action, reduction of side effects and improved

tolerability profile”

• “the S-enantiomer being effectively inactive”

 Not Perfect
• Maybe no advantage
• Unexpected adverse reactions
• Sotalol, (+) is 14 to 50 fold less active,
but enantiomers are equipotent in
antiarrhythmic activity. Increased
mortality in test group compared to
placebo and racemates.
• Highly unlikely that a drug company will
develop racemates of “failed” single
enantiomer
 Current Chiral Methods:
cost and time
• SEPARATION • SELECTIVITY
• Preparative • Chiral pool
chiral • A lot of
chromatograph catalysis
y • Enantioselectiv
• Cheaper e processes
despite waste • Conversion of
• Applicable to enantiomers
most
“Speed small
is essential, and you don’t always have the luxury of trying
chiral
to come up with the best synthesis”
 Despite Cost
• 2006, 80% of small-molecule drugs
approved by the FDA were chiral
• 75% were single enantiomers
• About 200 chiral compounds should
enter the market each year
• The field of asymmetric synthesis is
expanding rapidly, 50% of chiral drugs
use chiral technologies
• Due to FDA policy as of 1994, decision
to create racemic mixture must be
justified in quality, safety, and efficacy,
may be case-by-case
 Chiral Auxillaries
• Traditional synthesis of optically active compounds
results in a racemic mixture with equal amounts of
each enantiomer.
• Only one of the enantiomers has pharmacological
value. (i.e. thalidomide).
• Separating enantiomers from racemic mixtures is often
difficult and complicated.
• The use of chiral auxilliaries makes it possible to
synthesize only one of the two enantiomers.
• A chiral auxilliary is a chiral molecule that is attached
to the starting material during a synthesis that creates
the appropriate stereo-chemical environment so that
only one enantiomer is produced.

22
 Synthesis with Chiral Auxilliaries

A chiral auxiliary is a molecule that is temporarily incorporated into

an organic synthesis. Its asymmetry allows the formation of a
chiral intermediate followed by selective formation of one of two
stereoisomers depending on the reagent and/or reaction 23
conditions.
 Taxol

• The anti-cancer drug TAXOL is found in the Pacific

Yew tree, but there is not a sufficient supply to meet
demand.
• SinceTaxol is a very chiral molecule, one possibility
is to make it synthetically.
• The potential synthesis is very complicated and
would require using several chiral auxilliaries..
24
Thanks