Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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.