In the Classroom
A PDR Problem for Sophomore Organic Students Rosa Betancourt-Pérez Department of Chemistry, Box 23346, University of Puerto Rico, Río Piedras, PR 00931-3346;
[email protected] General Organic Chemistry at the Río Piedras Campus of the University of Puerto Rico is a required course for students who will continue studies in biology, pharmacy, medicine, and education. The course content has been restructured to include applications of organic principles to the medicinal sciences and the chemistry of consumer products. Before this revision, the course had the same content as most traditional organic chemistry courses (1) aimed primarily at chemistry majors. Although a few applications in related disciplines were mentioned, they were not thoroughly discussed. To provide ample time for the in-depth discussion of fundamental organic concepts, we have de-emphasized rote memorization of multistep organic syntheses. More time is now devoted to the mastery of topics and the development of skills that will facilitate the study and transfer of organic principles to subsequent courses in biochemistry, physiology and medicinal chemistry (2–4). Topics such as stereochemistry, molecular conformation, intermolecular interactions, solubility of weak acids and bases at physiological pH values, reactivity of functional groups, and reaction mechanisms are now covered in depth using biologically active compounds. More time is spent studying how the basic mechanisms of organic chemistry apply to the mode of action of specific drugs and biochemical species. We now include current articles, interactive demonstrations, and problems that increase students’ awareness of the organic chemistry that is present in healthrelated disciplines and in “real-world” chemistry. The following problem exemplifies our approach. It is assigned at the beginning of the second semester and requires students to study and interpret information in the Physician’s Desk Reference (PDR) (5) for various antiinflammatory drugs. It gives students an idea of how they can apply the knowledge acquired in the first semester of organic chemistry to understanding some principles of drug chemistry. The questions are related to stereochemistry, drug–enzyme interactions, solubility, and drug metabolism. This problem familiarizes students with the general terminology and nomenclature of drugs, the application of receptor-site topography in modern drug design, and the quantitative aspects of drug–receptor interactions. Typical student responses are included and important information is summarized in Table 1.
CH
CH3
H3C
CH3 COOH
CH-COOH
HC CH2 H3C
F
Ansaid
Motrin
Figure 1. The chemical structure of the drugs Ansaid (flurbiprofen) and Motrin (ibuprofen)
Before undertaking this problem, students study the stereochemistry of drugs and how spatial and chemical requirements for receptor interactions control drug activity (6–8). They read articles on chiral drugs, including one in which the analgesic properties of ibuprofen, the active ingredient in Motrin, are attributed to the S enantiomer (9, 10). They study the effects of alkyl groups, ketones, and halogens on the rate of electrophilic substitution reactions of aromatic compounds. They also study the metabolism of alkyl halides, aromatic compounds, alcohols, and amines (11–15). Along with this problem, they are given references on the aromatic hydroxylation reaction that liver enzymes carry out to increase the water solubility of drugs, which facilitates the removal of the chemical from the body and/or increases its biological activity (11, 13, 15). References are also provided on glucuronidation, an alternate mechanism of drug alteration in the body, and on chemical alterations that increase drug retention (8, 13, 15). A Comparison of Ansaid and Motrin This problem will guide you in the comparison of the drugs Ansaid (flurbiprofen) and Motrin (ibuprofen). The structures of these drugs are given in Figure 1. A copy of the information that appears on these drugs in the Physicians Desk Reference (PDR) has been included (5). Use this information and the references on reserve in the library to answer the following questions. You may find additional information on the Internet.
Question 1 Question. Describe the similarities and differences of the structures of these two drugs.
Table 1. Information on Ansaid and Motrin from the PDR Item
Ansaid
Motrin
Active Ingredient Common name Chemical name Chemical formula
flurbiprofen (+/{)-2-fluoro-α-methyl-[1,1′-biphenyl]-4-acetic acid C1 5 H1 3 FO2
ibuprofen (+/{)-2-( p-isobutylphenyl)propionic acid C1 3 H1 8 O2
Solubility in water, pH 7.0
slightly soluble
very slightly soluble
Clinical pharmacology
nonsteroidal antiinflammatory agent
nonsteroidal antiinflammatory agent
Dose
200–300 mg/day
2000–4000 mg/day
Major metabolites
4′-hydroxyl-flurbiprofen
25% (+)-2-[ p-(2-hydroymethylpropyl)-phenyl]propionic acid 37% (+)-2-[ p-(2-carboxypropyl)-phenyl]propionic acid
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Answer. These drugs are both acetic acid derivatives. Both have a stereogenic center that is substituted with a methyl group, a hydrogen, and an aromatic ring. In ibuprofen the aromatic ring is substituted with an isobutyl group and in flurbiprofen it is substituted with a fluorine and a phenyl group.
Question 2 Question. Describe the pharmacological activity of these drugs. They belong to a “group” of drugs referred to as the NSAIAs. What does this title mean? Answer. Both of these drugs have therapeutically useful antiinflammatory, antipyretic, and analgesic actions. They are classified as nonsteroidal antiinflammatory agents (NSAIAs). This classification is misleading, since they also have antipyretic and analgesic properties.
Question 3 Question. Ibuprofen is consumed as a racemic mixture, although the analgesic properties are attributed to only one of the enantiomers. Find out which enantiomer is active and draw its three-dimensional structure. Answer. Biological activity resides almost exclusively in the (S)(+)-isomer.
Question 4 According to a model for receptor stereochemistry, specific three-dimensional molecular interactions between a drug and a receptor attach a drug molecule to a cellular membrane. A receptor is a protein molecule that is imbedded in the cellular membrane. Part of its structure faces the outer part of the cell membrane. Although this surface is complicated, receptors have an area with the topography to bind certain drugs. When the drug fits into the receptor site a biological response may occur. Receptors are proteins. Proteins are polymeric chains of amino acids. Therefore, hydrogen bonds, dipole–dipole, dipole–ion, and ion–ion interactions and van der Waals forces are examples of interactions that can bind a drug to a receptor. For example, many drugs have aromatic rings. These “flat” rings can get very close to the “flat” surface of an receptor and van der Waals forces can bind them. Question. What molecular interactions could attract an receptor to Motrin? Could the same receptor bind to Ansaid? Draw the structure of the enantiomer of Ansaid that you would expect to bind and specify its absolute configuration. Answer. The α hydrogen and the carboxylic group can form hydrogen bonds. Van der Waals forces could attract the aromatic ring and the methyl group to hydrophobic areas of the receptor. The carbonyl group can bind to the amino acid chain via dipole–dipole and ion–dipole interactions. Since both drugs have similar stereogenic centers and biological activity, they probably bind to the same receptor. The S enantiomer of Ansaid would bind.
Question 5 Question. Compare the water solubility of Ansaid and Motrin. Identify the molecular interactions that could be present in water. Use drawings. Answer. Ansaid is more soluble than Motrin in water. The fluorine in Ansaid could be responsible, since it can hydrogen bond with water. 1102
Question 6 Metabolism is the process by which the body chemically transforms drugs. Most metabolism is carried out in the liver by enzymes. Metabolism occurs in the liver endoplasmic reticulum enzyme system. In vitro isolation of the endoplasmic reticulum from liver cells creates microsomes and this has led some scientists to refer to liver enzymes as “liver microsomal enzymes” (11, 13, 15). This term is misleading because there are no microsomes in living cells with liver endoplasmic reticulum enzyme. Metabolic reactions are either nonsynthetic or synthetic. In nonsynthetic reactions the drug can be chemically altered by (i) oxidation, (ii) reduction, (ii) hydrolysis, or (iv) a combination of these processes (12). In synthetic reactions the parent drug or an intermediate of a nonsynthetic reaction combines with an endogenous substance such as glucuronic acid to yield a conjugated product. The products of both nonsynthetic and synthetic metabolic reactions are more polar and are thus more readily excreted by the kidney (urine) and the liver (bile). Some of these products are biologically active (12). Question. What are the names of the major metabolites of Ansaid and Motrin? Draw their structures. These metabolites are more soluble in water than their parent compounds. Explain. Answer. All of these metabolites must be more water soluble than their precursors, since they can form more hydrogen bonds. Question 7 Glucuronide formation is one of the most common routes for conversion of a parent drug to a more watersoluble metabolite. The reaction involves the direct condensation of the drug with the activated form of glucuronic acid, uridine diphosphate glucuronic acid. Glucuronidation is catalyzed by liver enzymes. Glucuronides are eliminated in the urine and secreted in the bile. When a drug forms a glucuronide it becomes “conjugated”. Refer to the scheme in Figure 2, which illustrates the glucuronidation (conjugation) of acetaminophen (12, 13). Question. Are any of the metabolites of Ansaid and Motrin glucuronides? Draw the structure of a possible glucuronide of Motrin. Answer. According to the PDR, 14% of Motrin becomes conjugated, thus forming a glucuronide. Glucuronate-UDP forms an ester with Motrin to produce a glucuronide. Question 8 Another common route for the conversion of a parent drug to a more water soluble metabolite is the oxidation of aromatic compounds and their substituent alkyl groups.
COOH HO
COO-
OH O
H OH
H
H
OH
H
H
+ HO
O-UDP H
N
O
O H OH
H
H
OH
O
CH3 H
UDP-glucuronate
Acetaminophen
Figure 2. The glucuronidation of acetaminophen.
Journal of Chemical Education • Vol. 76 No. 8 August 1999 • JChemEd.chem.wisc.edu
N
Glucuronide of acetaminophen
O CH3
In the Classroom
These reactions are also catalyzed by liver enzymes. The metabolic oxidation of aromatic carbon compounds usually produces phenolic products and the position of hydroxylation can be influenced by the type of substituents on the ring, as observed in electrophilic aromatic substitution. For example, electron-donating substituents enhance ortho and para hydroxylation, whereas electron-withdrawing groups direct the hydroxylation to the meta positions (7, 13). Steric factors also play an important role, hydroxylation occurring at the least hindered position. Question. The main metabolite of flurbiprofen is hydroxylated in the 4′ position. Based on your knowledge of electrophilic aromatic substitution, explain why the hydroxylation did not occur on the ring bonded to fluorine. If the fluorine atom were replaced by a methyl group, what effect would it have on the position of hydroxylation? Answer. Fluorine deactivates the aromatic ring it is bonded to and hydroxylation occurs at the other, more activated, ring. A methyl group could activate the ring and direct hydroxylation to the 3 and 5 positions.
Question 9 Question. The metabolic hydroxylation of aromatic rings and of substituent alkyl groups increases the water solubility of drugs. In many cases, this increase in water solubility leads to a rapid removal of the chemical from the body. In a few cases, hydroxylation may increase the activity of a drug. According to the PDR, are any of these effects observed with these drugs? Explain. Answer. Hydroxylation of these drugs increases their water solubility and thus leads to their rapid removal from the body. The hydroxylated metabolites of these drugs do not demonstrate significant antiinflammatory activity. Question 10 The metabolic oxidation of groups attached to aromatic rings also increases the water solubility of drugs. Methyl groups attached to aromatic rings rapidly oxidize to water soluble carboxylic acids that are readily eliminated from the body. Methyl groups can be replaced by groups that are stable to oxidation to prolong the lifetime of the drug. For example, replacing the methyl group in the antidiabetic drug tolbutamide with a chlorine atom gave chlorpropamine, a much longerlasting drug (refer to Fig. 3). Halogenated hydrocarbons are not rapidly metabolized to water-soluble agents. Therefore, they tend to have a prolonged biological half-life (8, 13). Question. What is the maximum daily dosage of each of these drugs? Express these daily dosages in millimoles. The dosages differ by almost a factor of ten. Is the fluorine atom prolonging the effect of flurbiprofen? How?
CH3
O
O
S N H O
C
NH
CH2CH2CH3
Tolbutamide Cl
O
O
S N H O
C
NH
CH2CH2CH3
Chlorpropamide
Figure 3. Structures of tolbutamide and chlorpropamide
Answer. Fluorine resists oxidation and thus prolongs the biological half-life of flurbiprofen.
Question 11 Question. Look up the structures of aspirin and Oruvail (ketoprofen) in a PDR or on the Internet and compare them to Motrin and Ansaid. Are these drugs classified as NSAIAs? Which enantiomer of Oruvail is pharmacologically active? Answer. Both of these drugs are classified as NSAIAs. Only the S enantiomer of Oruvail is pharmacologically active. Question 12 Question. The metabolic fate of Oruvail is glucuronide conjugation. Aspirin undergoes hydrolysis to salicylic acid. Draw the structure of these metabolites. Is the main metabolite of aspirin biologically active? If so, what therapeutic properties does it have (12)? Answer. Salicylic acid is the main metabolite of aspirin and it has antipyretic, analgesic, and antiinflammatory properties. Question 13 Question. If you heard a physician say “You cannot take Ansaid because you are allergic to aspirin and Ansaid contains aspirin,” could you pick up an error in his statement? Explain. Answer. Yes, Ansaid does not contain aspirin. What he probably meant to say is that Ansaid, like most NSAIAs, triggers the same allergic (anaphylactic) reaction as aspirin. Therefore, someone allergic to aspirin should not take Ansaid. Concluding Remarks This problem is assigned to students in cooperative groups. Each group is provided with a copy of the product information that appears in the PDR on Ansaid, Motrin, and Oruvail. References that describe the metabolism of aromatic hydrocarbons, the chemical transformations that increase drug retention, and the spatial and chemical requirements for drug–receptor interactions are made available (7, 8, 11–15). Our students find this problem interesting and challenging, and in general, their responses are accurate. Some are intimidated at first, since it is the first time they are required to apply their chemical knowledge to a new situation: the study of the organic principles involved in the biological activity of drugs. Others have some difficulty recognizing the effect of fluorine on the rate of metabolism and position of hydroxylation of Ansaid. Students’ evaluations state that this problem got them to search the library and the Internet for other sources of information, to apply chemical knowledge to solve a “real” problem, and to read and interpret PDR material as “chemists”. They feel that after this experience, they will always look into and study product inserts before they ingest any medication. As pointed out by E¯ge et al. (16 ), there are skills and mental processes that go beyond the mastery of content, but are expected of a college graduate. Of those suggested, this type of problem encourages students “to engage in the kinds of sideways thinking that comes from learning many ways to look at things, and to experience the fit of form with function.” Those students who “see” the structural similarity of these drugs, who can transfer the knowledge of the effect of deactivating groups in electrophilic substitution to explain a
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longer elimination half-life, and who are able to integrate such seemingly different concepts will have taken an important step in preparation for future studies in biomedical sciences. Literature Cited 1. 2. 3. 4. 5.
Johnson, A. W. J. Chem. Educ. 1990, 67, 299–303. Craig, C. R. J. Chem. Educ. 1982, 59, 231. Peterson, J. A. J. Chem. Educ. 1982, 59, 601. Harrison, A. M. J. Chem. Educ. 1989, 66, 825–826. Physician’s Desk Reference, 49th ed.; Medical Economics: Montvale, NJ, 1995. 6. Korolkovas, A. Essentials of Medicinal Chemistry; Wiley: New York, 1988. 7. Bruice, P. Y. Organic Chemistry; Prentice Hall: Upper Saddle River, NJ, 1998; pp 204, 1244–1247.
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8. Patrick, G. L. An Introduction to Medicinal Chemistry; Oxford University Press: Oxford, 1995. 9. Thall, E. J. Chem. Educ. 1996, 73, 481–484. 10. Stinson, S. C. Chem. Eng. News 1992, 70(Sep 28), 46–77. 11. Lemke, T. L. Review of Organic Functional Groups; Lee and Febijer: Philadelphia, 1988. 12. The Merck Manual for Diagnosis and Therapy; Berkow, R., Ed; Merck: Rahway, NJ, 1992; pp 2607–2609. 13. Foye, W.; Lemke, T.; Williams, D. Principles of Medicinal Chemistry; Williams and Wilkins: Media, PA, 1995. 14. Medicinal Chemistry, Principles and Practice; King, F. D., Ed; The Royal Society of Chemistry: Cambridge, 1994; pp 86–93. 15. Goodman and Gilman’s The Pharmacological Basics of Therapeutics; Hardman, J. G.; Limbird, L. E., Eds.; McGraw Hill: New York, 1996. 16. E¯ge, S.; Coppola, B.; Lawton, R. J. Chem. Educ. 1997, 65, 623.
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