After completing this chapter, students will be able to
Discuss the differences among single, double, and triple bonds.
Correctly number alicyclic and heterocyclic rings, sugars, and steroids.
Correctly designate α, β, and ω positions on drugs and biomolecules.
Correctly identify ortho, meta, and para positions on an aromatic ring.
Correctly explain how peptides are constructed from amino acids.
Correctly identify the components of nucleosides and nucleotides.
This text focuses on the fundamental concepts that govern the discipline of medicinal chemistry as well as how and why these concepts are essential in therapeutic decision making. In very simplistic terms, medicinal chemistry can be defined as the chemistry of how drugs work. In other words, it is the discipline that seeks to identify the specific atoms or functional groups that are responsible for specific biological/biochemical actions. To illustrate this point, let’s compare the structures and dosing of two commonly used drugs, ibuprofen and naproxen.
Both of these drugs are available without a prescription (i.e., over-the-counter [OTC]) and produce anti-inflammatory, analgesic, and antipyretic actions. Ibuprofen is a shorter-acting drug and must be administered every 4 to 6 hours, whereas naproxen is a longer-acting drug that can be dosed every 12 hours. In evaluating these chemical structures, it is found that there are both similarities (i.e., carboxylic acid and adjacent methyl group) and differences (i.e., bicyclic ring with a methoxy group versus monocyclic ring with an alkyl chain). The discipline of medicinal chemistry seeks to explain how these structural (i.e., chemical) differences result in different durations of action. Once this relationship is established, this information can be used to predict the relative durations of action of other agents within this chemical/pharmacological class.
The primary goal of this text is to help the reader develop a solid foundation in medicinal chemistry. Once this foundation has been established, the reader should be able to analyze drug structures and understand how their composite pieces can contribute to the overall properties and/or activity of the drug molecules. Every drug that is prescribed and dispensed is a chemical structure with a specific composition. The atoms and functional groups that comprise these chemical structures dictate the route of administration, the duration of action, the pharmacological actions, and the presence or absence of specific adverse drug reactions or drug interactions.
The organization of topics within this text has been carefully selected to allow the reader to progressively gain knowledge about the chemistry of drug molecules. Each chapter builds on another and, when applicable, relevant examples are cross-referenced. The authors of this text assume that the reader has a basic understanding of inorganic chemistry, organic chemistry, and biochemistry. When applicable, key concepts from these disciplines are reviewed as they apply to medicinal chemistry.
Because every atom within the drug structure is part of a specific functional group, we chose functional group identification and evaluation as the starting point of our discussion. In Chapter 2, we focus on the chemical characteristics of functional groups and the roles they can play in drug action. From there, Chapter 3 examines those functional groups that can be classified as either acidic or basic. We also explore the reasons why it is important to know the acid/base character of a drug molecule. In Chapter 4, we continue our examination of acidic and basic functional groups via introduction of the Henderson-Hasselbalch equation and review of several strategies for solving quantitative and qualitative pH and pKa problems. Numerous examples are provided throughout that chapter to help the reader become more proficient in solving these types of problems. Similar to Chapter 3, we devote the end of Chapter 4 to selected examples designed to help the reader understand the importance of pH, pKa, and ionization in drug therapy. In Chapter 5, we discuss how acidic and basic functional groups can form inorganic and organic salts. Additionally, we discuss how these salts influence the water/lipid solubility of a drug molecule and how this relates to various routes of administration. An emphasis is also placed on the need for a balance between water and lipid solubility and the ability to analyze a drug molecule to discern its water and lipid soluble components. The chapter ends with strategies to optimize either the water or lipid solubility of a drug molecule and the associated pharmaceutical and therapeutic advantages.
In some respects, Chapters 2 through 5 share a common thread because they sequentially discuss the roles and properties of functional groups as a whole, identify those that are acidic or basic, review a strategy to calculate the extent to which they are ionized in a given environment, and then examine how all of these characteristics contribute to the overall solubility of a drug molecule. This is extremely important for ensuring that a drug molecule can be administered to a patient via the desired route (e.g., orally, via intravenous [IV] injection, or via nasal inhaler).
In Chapter 6, we examine the types of binding interactions that can occur between a drug molecule and its biological target. Examples of each type of interaction are provided to allow the reader to become more proficient at analyzing drug molecules and identifying the types of interactions that can occur with each of its functional groups. In Chapter 7, we discuss how the stereochemistry of a drug molecule can affect its interaction with biological targets. We review chirality, stereochemical designations, and the differences between enantiomers, diastereomers, geometric isomers, and conformational isomers. A major emphasis is placed on the pharmacological and therapeutic differences that can occur between enantiomers as well as the specific advantages associated with conformational restriction of a drug molecule.
In Chapter 8, we discuss the purpose of drug metabolism and explore the metabolic transformations by which enzymes in the liver and other organs and tissues chemically alter drug molecules. The chapter includes mechanisms and examples for each type of metabolic transformation and identifies the functional groups that are susceptible to each type of transformation. Similar to Chapter 6, the overall objective is to provide sufficient detail to the reader, such that he or she becomes more proficient at predicting possible metabolic transformations and understanding known metabolic pathways for a given drug molecule.
In Chapter 9, we introduce the concept of structure activity relationships (SARs) and relate this to many examples discussed in previous chapters. Although SARs are an essential component of the discipline of medicinal chemistry, we intentionally reserved the discussion of this topic until after the other concepts were discussed. Taken literally, an SAR defines the relationship between the chemical structure of a drug molecule (or one or more of its component functional groups) and the physicochemical or pharmacological effects it produces. As such, the text introduces the types of relationships (e.g., ionization, solubility, drug binding interactions, stereochemistry, and metabolism) prior to discussing SARs. We close the chapter with an overview of some basic concepts of molecular modification so the reader will understand the common strategies used in the design of new drug molecules as well as analogs of currently approved drugs.
The final chapter focuses on what we call “Whole Molecule Drug Evaluation,” a process that requires the reader to use the evaluation skills discussed in the first nine chapters to fully assess specific attributes of known drug molecules. Unlike the end-of-chapter review questions that focus on one or two chapter-specific concepts, this final chapter emphasizes an overall analysis of individual drug molecules.
Each chapter includes a variety of examples and review questions chosen to illustrate and reinforce the concepts discussed. Additionally, Chapters 2 through 9 include Structural Analysis Checkpoint questions. These questions follow specific drug molecules throughout each of these chapters and sequentially probe their chemical nature as new concepts are presented. Answers are provided in the Appendix for all questions so readers can assess their understanding of the concepts that are presented. With perhaps a few exceptions, all examples and review questions are based on currently available drugs. The text is designed to be comprehensive with regard to the fundamental chemical concepts that govern drug action. Through conceptual discussions, examples, and applications, the text is designed to provide readers with the knowledge and skills to predict, discuss, and understand the pertinent chemistry of any drug molecule or class of drug molecules encountered.
Two resources are provided below. They have been placed in this introductory chapter for easy access. The first resource is a review of some selected chemical nomenclature and numbering that are used throughout the text. The second resource is a listing of references used in the writing of this text.
REVIEW OF SELECTED NOMENCLATURE AND NUMBERING
The following topics have been selected due to their relevance in naming and numbering specific atoms and groups in drug molecules. For a full discussion of organic chemistry and/or biochemistry nomenclature, please consult the suggested references listed at the end of this chapter.1–17
Orbital Hybridization and Bond Formation
Carbon atoms within the structure of a drug molecule are able to form single, double, or triple bonds with one another or with other atoms, such as oxygen, nitrogen, sulfur, and halogens. For this to occur, the 2s and 2p orbitals must form hybrid orbitals consisting of one s orbital and either one, two, or three p orbitals. Single bonds are comprised of sp3 hybrid orbitals and form a tetrahedral shape with bond angles of approximately 109.5°. Double bonds are comprised of sp2 hybrid orbitals and form a planar shape with bond angles of approximately 120°. There are two components to a double bond: an initial overlap of the two sp2 orbitals and a side-to-side overlap of the unhybridized p orbitals, known as a π bond. Triple bonds are comprised of sp orbitals and form a linear shape with bond angles of 180°. Similar to double bonds, there are several components to a triple bond: an initial overlap of the two sp orbitals and two orthogonal (i.e., at right angles) π bonds formed by the two sets of unhybridized p orbitals.
The concept of hybrid orbitals also applies to nitrogen and oxygen atoms; however, due to the presence of additional electrons, a nitrogen atom contains one lone pair of nonbonding electrons while oxygen contains two lone pairs of nonbonding electrons. The hybrid orbitals of these atoms have a similar shape; however, the bond angles are slightly different due to the lone pairs of electrons. Nitrogen is able to form single bonds with carbon, oxygen, nitrogen, and hydrogen; double bonds with carbon, oxygen, and nitrogen; and triple bonds with carbon. Oxygen is able to form single bonds with carbon, nitrogen, and hydrogen or double bonds with carbon and nitrogen.
Numbering of Alicyclic Rings
An alicyclic ring is comprised of hydrocarbon. It may contain double bonds, but it cannot be aromatic. The attachment point of an alicyclic ring such as cyclohexane or cyclopentane to a drug molecule is designated as the C1 carbon of the ring. When a substituent (i.e., functional group) is attached to the ring, its attachment point is assigned the lowest possible number, as shown below. This also holds true whenever two or more ring substituents are present.
Designation of Aromatic Ring Positions
The designations ortho, meta, and para are commonly used to indicate the positions of substitution on an aromatic ring. These designations are relative to the attachment point of the aromatic ring to the rest of the drug molecule. This attachment point is known as the ipso carbon or the C1 position. As shown below, an ortho designation represents a 1,2 substitution pattern on a benzene ring, a meta designation represents a 1,3 substitution pattern, and a para designation represents a 1,4 substitution pattern. In looking at the 2-methyl, 4-hydroxyl substituted ring, please note that the 2-methyl group is located ortho to the rest of the drug molecule, the 4-hydroxyl group is located para to the rest of the drug molecule, and the 2-methyl and 4-hydroxyl groups are located meta to one another (i.e., relative to one another, they are in a 1,3 substitution pattern or meta to one another). As seen with this last example, these designations can get more complicated with multiple substituents and multiple aromatic rings. In some cases there may be more than one ipso carbon, and a functional group could be ortho to one ipso carbon and meta to another. Readers who desire a more in-depth discussion of this topic are referred to the texts by either Graham Solomons et al9 or Dewick10 cited at the end of this chapter.
Numbering of Heterocyclic Rings
A heterocyclic ring contains atoms other than just carbon and hydrogen (i.e., heteroatoms). The three most prominent heteroatoms found in these rings are nitrogen, oxygen, and sulfur. When there is only one heteroatom present within the ring, it is designated as atom “1” in the ring. Similar to alicyclic rings, substituents are assigned the lowest possible number. When there are similar heteroatoms present within the ring (e.g., two nitrogen atoms), one of these is assigned as atom “1” and the other is assigned the next lowest number in sequence around the ring. When there are two different heteroatoms present within the ring, the heteroatom with the highest priority is designated as atom “1,” and the other is assigned the next lowest number. Priority is determined by molecular weight; therefore, sulfur has the highest priority, oxygen has the second highest priority, and nitrogen has the lowest priority. Some examples are shown below. For additional examples of heterocyclic rings and their numbering, please consult the text by Lemke et al1 referenced at the end of this chapter.
Two common heterocyclic rings are the pyrimidine and purine rings seen in DNA and RNA. The numbering of these ring systems is shown below.
Numbering of Sugars
Sugars are classified as either aldoses or ketoses depending on the presence of an aldehyde or a ketone, respectively. If the sugar is an aldose, the aldehyde carbon is always designated as carbon “1,” and the other carbon atoms are sequentially numbered, as shown below with the examples for glucose and ribose. If the sugar is a ketose, it is numbered beginning at the terminal carbon atom that is closest to the ketone. In most instances, the ketone carbon is at the “2” position, as shown below with fructose.
Sugars can readily assume cyclical structures. The hydroxyl groups within a sugar molecule can react with either the aldehyde or ketone to form a hemiacetal or a hemiketal, respectively, as shown in Figure 1-1. Although it is possible for any hydroxyl group within the structure of the sugar to form this cyclical structure, those that form either five or six membered rings are most common. A five-member ring for a sugar is known as a furanose ring, while a six-member ring is known as a pyranose ring. The numbering does not change; however, the stereochemistry of the carbon atom used to make the hemiacetal or hemiketal can be either α or β, as described in the next section. Shown in Figure 1-1 are the cyclical versions of glucose, ribose, deoxyribose, and fructose.
Alpha (α), Beta (β), and Omega (ω) Designations
These designations are used to identify specific carbon atoms within the structure of a drug molecule. The α designation is used to indicate a carbon atom that is located directly adjacent to a carbonyl group (C=O) or a heteroatom, whereas the β designation is used to indicate the next carbon atom in the chain. Occasionally, γ and δ are used to indicate the third and fourth carbon atoms in a chain. This represents an alternative way to number carbon atoms. As you progress though different classes of drug molecules, you will discover that some drug molecules use conventional Arabic numerals (e.g., 1, 2, 3) to number carbon atoms, whereas others use these Greek letter designations.
Figure 1-2 provides several examples of drug molecules that use the α/β designation. Both ibuprofen and naproxen contain a methyl group directly adjacent to a carboxylic acid. This methyl group is located at an α position, and these drugs are chemically classified as α-methylarylacetic acids. The carbon atom directly adjacent to the primary amine of dopamine is designated as α, while the next atom in this ethyl chain is designated as β. The addition of a methyl group directly adjacent to the primary amine produces α-methyldopamine. As illustrated with penicillin G and ampicillin, a single molecule can have more than one α designation. Both of these drugs contain a β-lactam ring and are classified as β-lactam antibiotics. This designation comes from the fact the nitrogen atom that is involved in the lactam bond is attached to the carbon atom that is β to the carbonyl.
The α/β designations are also used for cyclical sugars. Whenever an aldehyde or a ketone forms a hemiacetal or a hemiketal, a new stereochemical center is also formed. This stereochemical center is unique in that reversible reactions can easily convert linear sugars to cyclical sugars, and vice versa, allowing the chiral center to easily change. This process is known as mutarotation, and the chiral carbon atom is known as the anomeric carbon. Isomeric forms of sugars that differ only in the stereochemistry of the anomeric carbon of hemiacetals and hemiketals are known as anomers. The α and β designations for the stereochemistry of the anomeric carbon are based on a comparison of the stereochemistry of the anomeric carbon to the stereochemistry of the chiral center that is furthest away from the anomeric carbon. While this can get a little complicated, there is an easy way to remember these designations with the most commonly encountered sugars (e.g., glucose, ribose, deoxyribose, fructose, and galactose). Whenever, the hydroxyl group is “down,” it is designated as α, and whenever the hydroxyl group is “up,” it is designated as β. Examples using glucose and ribose are shown below.
The ω designation is used to identify the carbon atom that is located at the end of an alkyl chain. Additionally, the designations ω-1, ω-2, and so on are used to designate carbon atoms that are sequentially positioned one or two atoms (or more) from the end of an alkyl chain.
The following designations are used to identify enantiomers and chiral centers. Please note that the term enantiomer refers to the drug molecule as a whole, while a chiral center is a single carbon atom. A complete discussion of these designations can be found in Chapter 7.
(+)/(-): These designations identify the direction in which an enantiomer rotates plane polarized light. The (+) designation indicates that the enantiomer rotates plane polarized light to the right, or clockwise, while the (−) designation indicates that the enantiomer rotates plane polarized light to the left, or counterclockwise.
d/l: These designations are similar to the (+)/(−) designations. The d designation is an abbreviation for dextrorotatory and indicates that the enantiomer rotates plane polarized light to the right, or clockwise. The l designation is an abbreviation for levorotatory and, similar to the (−) designation, indicates that the enantiomer rotates plane polarized light to the left, or counterclockwise.
d/l: These designations refer to the absolute configuration, or steric arrangement, of the atoms about a given chiral carbon atom. The d/l designations are linked to the stereochemistry of d- and l-glyceraldehyde, and their use is primarily limited to stereochemical designations of sugars and amino acids.
R/S: Similar to d/l designations, R/S designations refer to the absolute configuration of atoms about a given chiral carbon atom. These designations are preferred over the d/l designations because they can be assigned via the use of unambiguous sequence rules developed by Cahn, Ingold, and Prelog.
α/β: These designations also refer to the absolute configuration of atoms about a chiral carbon atom; however, their use is primarily limited to steroids and glycosidic bonds. When used with steroids, the α designation is used for functional groups projected away from the viewer (represented as dashed lines), while the β designation is used for functional groups projected toward the viewer (represented as solid lines).
The α and β designations for glycosidic bonds follow the guidelines discussed above for cyclical sugars. An example is shown in Figure 1-3 using the α and β isomers of methyl glucopyranoside. A further discussion of the stereochemistry of glycosidic bonds can be found in any of the biochemistry texts referenced at the end of this chapter.
Endogenous steroids are all derived from cholesterol and contain four rings labeled A through D, as shown in estradiol (Figure 1-4). The tetracyclic steroid nucleus consists of 17 carbon atoms and is numbered as illustrated with cholesterol. The numbering begins in the A ring and moves counterclockwise around the A and B rings (C1 through C10), clockwise around the C ring (C11 through C14), and then counterclockwise around the D ring (C15 through C17). All endogenous, synthetic, and semisynthetic steroids share this 17-atom backbone. The methyl groups attached to the C13 and C10 atoms are designated as C18 and C19, respectively, and the side chain attached to the C17 atom begins with the C20 designation and is sequentially numbered, as shown in cholesterol.
The stereochemistry at the C8, C9, C10, C13, C14, and C17 positions for all estrogens, androgens, progestins, glucocorticoids, and mineralocorticoids is the same as that shown in estradiol, cholesterol, and testosterone (Figure 1-4). The only exception here is that the C10 position of estrogens (e.g., estradiol) is part of an aromatic A ring and therefore not chiral. Please note that the hydrogen atoms attached to C8, C9, and C14 are often not shown in steroid structures but are assumed to be present, as shown in estradiol. The hydrogen atom attached to the C8 position always has β stereochemistry, and the hydrogen atoms attached to the C9 and C14 positions always have α stereochemistry. The naturally occurring functional groups attached to the C10, C13, and C17 positions always have β stereochemistry. The C5 carbon is normally part of an aromatic ring, as seen with estradiol, or a double bond, as seen with cholesterol and testosterone. If the double bond is reduced, the stereochemistry of the C5 substituent must be indicated, as shown with 5α-dihydrotestosterone.
A relatively small number of drugs are peptides or peptide mimics or include a peptide component as part of their structure. Peptides are comprised of amino acids. Each amino acid consists of a basic amine, an α carbon that is attached to the side chain of the amino acid, and a carboxylic acid. As previously mentioned, the α designation is assigned because the carbon atom is directly adjacent to a carbonyl atom (i.e., the carboxylic acid). A brief overview of all 20 naturally occurring amino acids is provided in Chapter 2.
A peptide is a polymer that consists of two or more amino acids that are linked together by amide bonds (aka peptide bonds). A dipeptide consists of two amino acids, a tripeptide consists of three amino acids, and so forth. By convention, peptide sequences are normally drawn with the amino end on the left and the carboxyl end on the right, and peptide sequences are normally read left to right, or amino terminus to carboxyl terminus. Exceptions to this occur with cyclical peptides because they don’t contain right or left ends. Examples of a tripeptide and an octapeptide are shown in Figure 1-5. The individual amino acids have been highlighted in the tripeptide for the reader to better identify the repeating Nitrogen—α Carbon (with side chain)—Carbonyl sequence present in peptides and proteins. This triad sequence represents the universal pattern of amino acid building blocks. Recognition of this sequence is essential for the correct reading of a peptide or peptide mimic. The amino terminus, the carboxyl terminus, and a sample peptide bond have been highlighted with boxes in the octapeptide.
There are a large number of enzymes within the human body that catalyze the cleavage of proteins and peptides at specific sites. The designations P1 and P1′ are used to indicate the site of cleavage, with the P1 designation corresponding to the amino acid that contains the carbonyl group and the P1′ designation corresponding to the amino acid that contains the nitrogen atom. The numbering of adjacent amino acids incrementally increases with the P2, P3, P4, etc., designations incrementally moving to the left (or toward the amino end) and the P2′, P3′, P4′, etc., designations incrementally moving to the right (or toward the carboxyl end). As an example, let’s examine the octapeptide shown in Figure 1-5. If it is enzymatically cleaved between the valine and tyrosine residue, then the following designations would be assigned.
These designations are important when evaluating drug molecules that inhibit a specific enzyme by acting as a peptide mimic. As an example, let’s look at enalaprilat, a tripeptide mimic that inhibits the enzyme angiotensin converting enzyme (ACE). This enzyme is relatively nonspecific and can cleave dipeptide residues from the carboxyl terminus of a peptide. It is therefore classified as a dipeptidyl carboxypeptidase. Its primary action is to cleave angiotensin I, an inactive decapeptide, to angiotensin II, an octapeptide that, when bound to its receptor, is a potent vasoconstrictor. Inhibition of this enzyme by enalaprilat prevents the biosynthesis of angiotensin II and therefore is useful in the treatment of hypertension and other cardiovascular disorders. As illustrated in Figure 1-6, the cleavage site of angiotensin I is located between the phenylalanine and histidine residues. Thus, the P1 designation is assigned to phenylalanine and the P1′ designation is assigned to histidine. The other amino acids are designated according to the guidelines described above. Enalaprilat mimics the carboxyl terminal Phe—His—Leu sequence of angiotensin I. Because ACE is a relatively nonselective dipeptidyl carboxypeptidase, it can interact with enalaprilat. The phenylalanine of enalaprilat mimics the P1 amino acid, while alanine and proline mimic the P1′ and P2′ amino acids.
NUCLEIC ACID NOMENCLATURE
A number of drugs that are used to treat cancer, viral infections, and other disease states are structural analogs of naturally occurring nucleosides and nucleotides that comprise the structures of ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). A nucleoside consists of a nitrogenous base (either a purine or a pyrimidine) and a sugar (either ribose, naturally found in RNA, or deoxyribose, naturally found in DNA). The addition of one or more phosphates to a nucleoside results in a nucleotide. The two common purines are adenine and guanine, while the three common pyrimidines are cytosine, thymine, and uracil. The names of these purines and pyrimidines change slightly whenever they are part of a nucleoside or a nucleotide. Since you will encounter these nucleoside and nucleotide analogs, a review of the nucleic acid nomenclature is summarized in Table 1-1.
The names in parentheses are commonly used to designate the ionized form of the monophosphates. Nucleotides can also be diphosphates and triphosphates.
REFERENCES CONSULTED AND RECOMMENDED
The following references were consulted in the preparation of this text. The text by Lemke et al1 is recommended to those readers who desire a more in-depth explanation of the organic chemistry of functional groups. Foye’s2,3 texts and the Wilson and Gisvold4 text are recommended for those readers who wish to learn more about the medicinal chemistry of specific drug molecules and specific classes of drug molecules. These texts are organized according to major drug classes (e.g., cholinergic agents, sedative/hypnotic agents, diuretics) and therapeutic uses (i.e., indications) and are comprehensive in their discussions of the medicinal chemistry of currently available drugs. The Essentials of Foye’s Principles provides bullet point explanations of each drug and drug class and is much more “student-friendly” than classic textbooks. The Renslo text discusses some medicinal chemistry concepts; however, it is more focused on organic chemistry than medicinal chemistry.5 The Silverman and Hollady6 and Burger’s7 texts are a little more advanced in their coverage of medicinal chemistry; however, they are both excellent resources for the topics of drug design and drug development. They are recommended for those readers who desire extended discussions in these areas. The Goodman & Gilman’s8 text is also a valuable resource. Although it is primarily a pharmacology text, it nicely integrates pharmacology with both medicinal chemistry and therapeutics. It provides in-depth information regarding the mechanisms of action for all drugs and drug classes and is a nice complement to both the Foye and Wilson and Gisvold texts. The Graham Solomons et al,9 Dewick,10Lehninger,11 and Berg et al12 texts are recommended for those readers who desire a review of specific organic chemistry or biochemistry topics. Clinical Pharmacology,13 Facts and Comparisons,14 Lexicomp,15 and Micromedex16 are excellent online resources for drug information. Each of these references contains comprehensive information for each commercially available drug. DrugBank17 is a valuable resource for chemical properties of drugs. Along with Foye’s2,3 texts, these resources provide the vast majority of individual pKa values for specific functional groups within the structures of drug molecules.