Download Module B - Core Content Activity 1: A journey from the

4-H Club 1
Module B - Core Content Activity 1: A journey from the dark side into the light
Problems:
1. A structural formula of thalidomide is shown below. Thalidomide is an example of a chiral drug. There are 13
carbon atoms in this structure but only one of them is chiral (for location, see problem 2). Rationalize why.
The chiral atom in thalidimide is the dotted carbon because it has three different atoms attached to it
(nitrogen, hydrogen, a CO functional group and a carbon). It has four different atoms or groups of
atoms attached to it. The second carbon attached to the chiral atom is double bonded to an oxygen atom
which changes the priority of that carbon atom. The two enantiomers are optical but cannot be
superimposed making them chiral.
2. Shown below are perspective diagrams of the enantiomers (also called optical isomers) of thalidomide. The
single chiral carbon atom in this structure is indicated by a dot (problem 1 had you think about why this
particular carbon is chiral). Assign the correct chiral configuration for each of the structures shown below. In
other words, identify the structure that is R-thalidomide and the structure that is S-thalidomide. Illustrate (using
a perspective or Newman diagram) and explain (with reference to your diagram) how you arrived at your
assignments.
Thalidimide-1, through the moveable 3D molecule computer program, is the S-thalidimide because the
priority direction of the attached atoms is counter clockwise. And the thalidimide-2 is the Rthalidimide because the priority direction of attached atoms is clockwise. For each molecule we
looked down the chiral atom and the bond axis to the lowest priority atom(H) to determine the
direction of the priority atoms from Nitrogen to CO group to the final Carbon.
Thalidomide – 1
Thalidomide – 2
4-H Club 2
3. Historically, thalidomide caused severe birth defects in the late 50s and early 60s, primarily in countries
throughout Europe and Africa, when taken by pregnant women during the first trimester. (Phocomelia, or
absence of the long bones, was a prevalent type of birth defect seen with this drug – see picture on page 1).
Describe the historical events and issues that led to thalidomide (an example of a teratogen, or chemical that
causes birth defects) being given to pregnant women throughout Europe, but not in the U.S.
Use reference b on page 1 to answer this problem.
Dr. Kelsey was very specific in her analysis of the data for thalidomide
Oct. 1, 1957: thalidomide introduced in Germany (Contergan was the brand name) by
Chemie Grünenthal as a sedative for use in treating insomnia as well as to reduce nausea
during pregnancy. Some testing had been done on rodents but they metabolize the drug differently
than humans. Most countries at the time did not require research and evidence prior to releasing the
drug for sales.
1960: the drug is widely used in Europe and Africa by more than 20 countries for these
purposes
1960: Frances Oldham Kelsey was named reviewing medical officer at the Food & Drug
Administration. Her first assignment was thalidomide. Richardson-Merrell Inc. submitted
a New Drug Application to market thalidomide in the U.S. under the brand name
Kevadon. The prevailing law was the 1938 Federal Food, Drug & Cosmetic Act, which
required proof of safety to be submitted to FDA before a drug could be approved for
marketing. This was vastly different than in most European countries. She insisted on
more proof from the drug company and ultimately prevented the drug’s approval in the
U.S.
Nov. 18, 1961: Welt am Sonntag, a German paper, reported that pregnant women who
had been taking thalidomide were giving birth to babies with gross deformities.
November 27,1961: Grünenthal pulls the drug off the market
March 8, 1962: Richardson-Merrell withdrew its drug application, after the effects were
widely publicized.
Today: All countries have laws similar to those in the United States for testing and
evidence for the safe use of a drug prior to approval.
4-H Club 3
4. Thalidomide was orally administered as a racemic mixture (as, for example, Ibuprofen and Ritalin are today). In
one proposal, the R form of thalidomide has a sedative action and relieves morning sickness in pregnant women,
whereas the S form is the teratogen. One of your colleagues argues that the tragedy of deformed births could
have been averted if the R form was first separated from the S form using chiral chromatography, and then
marketed as optically pure R to the public. Evaluate this proposal using chemical argument and structural
illustration.
Lab tests after the tragedy revealed that the 'S' enantiomer was tetragenic but the 'R' isomer
was an effective sedative. Some thought that the safe enantiomer could be manufactured and only
that form could be sold. Technology is now available to isolate the optically pure ‘R’ or ‘S’. We now
know that even when only one of the optical isomers is created, if administered, the pH in the body
can cause racemizing. This means that both enantiomers are formed in a roughly equal mix in the
blood. Once in the body forms both, ‘S’ and ‘R’ are formed. So, even if a drug of only the 'R' isomer had
been created, the body would have produced the other enantiomer and the disaster would still occur.
There are four different groups on the chiral atom and cannot be superimposed. That leaves us with
the following structure which is Sp3 oriented, 3 dimensional with each angle being 109 degrees. This
forms a tetrahedral structure.
If the carbon – hydrogen bond breaks we lose a hydrogen ion, which is H+ and the carbon becomes Cand behaves as an acid. The following structure is Sp 2 oriented, 2 dimensional with each angle at 120 degrees.
This forms a hybridized trigonal plane. If the H+ wants to rebond with the C- it can come in on either side.
Depending on which side it comes in on it will form either the ‘R’ or the ‘S’. Because of this racimization it lead
to the question is ‘S’ or ‘R’ really safe?
4-H Club 4
5. Despite the notorious legacy associated with the thalidomide drug, the FDA gave approval in 1998 to a company
called Celgene to market thalidomide in the U.S. under the brand name Thalomid.
Use reference b on page 1 to answer problem 5a.
a. There is only one disease that has received FDA-approval for the use of thalidomide as a treatment.
Identify this disease, and list the major provisions of Celgene’s STEPS program that govern the current
use of thalidomide in patients.
Erythema nodosum leprosum, the disease is known as leprosy. Thalomid is effective for this
disease because of its anti-inflammatory properties. Thalomid is a well-known teratogen and
therefore the FDA also imposed severe restrictions on the drug's distribution. The major
provisions are called the STEPS program. Only doctors registered with Celgene's STEPS (System
for Thalidomide Education & Prescribing Safety) program can prescribe the drug. Prescriptions
can not to be given to female patients unless a negative pregnancy test is attained within 24
hours of the beginning of treatment. Female patients must take pregnancy tests regularly for a
prescribed period and must use two reliable forms of contraception while under treatment. Male
patients are instructed to use condoms during intercourse because it is unknown whether
thalidomide in sperm or semen affects fetal development.
b. Celgene is seeking FDA approval for Revlimid, a chiral chemical derivative of thalidomide. List a
structural formula for Revlimid (use, for example, the PubChem database, introduced in Module A) and
discuss the chemical group additions or deletions that were made to the structure of thalidomide using
correct terminology.
(For example: A carboxyl group was added; an amide group was deleted…)
Revlimid - C13H13N3O3
Thalidomide - C13H10N2O4
An amine group was added to the Thalidomide to get Revlimid.
A carbonyl group was deleted from the Thalidomide to get Revlimid.