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4 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
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
CH 1 - INTRODUCTION 5
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
6 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
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 fivemember 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.
FIGURE 1-1.Examples of a hemiacetal, a hemiketal, and the cyclical structures of some
common sugars.
Alpha (`), Beta (a), and Omega (v) 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
CH 1 - INTRODUCTION 7
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.
FIGURE 1-2.Examples of ` and a designations.
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,”
8 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
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.
Stereochemical Designations
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.
y (+)/(-): 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.
y 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.
y /: These designations refer to the absolute configuration, or steric arrangement, of the
atoms about a given chiral carbon atom. The / designations are linked to the stereochemistry of - and -glyceraldehyde, and their use is primarily limited to stereochemical
designations of sugars and amino acids.
y R/S: Similar to / designations, R/S designations refer to the absolute configuration of
atoms about a given chiral carbon atom. These designations are preferred over the / designations because they can be assigned via the use of unambiguous sequence rules developed by Cahn, Ingold, and Prelog.
y `/a: 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).
CH 1 - INTRODUCTION 9
y 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.
FIGURE 1-3.An example of ` and a glycosidic bonds.
Steroid Nomenclature
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.
Peptide Designations
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
10 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 1-4.Standard numbering and designations for steroid based drug molecules.
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—` 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
CH 1 - INTRODUCTION 11
FIGURE 1-5.Examples of a tripeptide and an octapeptide.
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.
12 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 1-6.Angiotensin I and enalaprilat with cleavage site designations.
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.
TABLE 1-1.Nucleic Acid Nomenclature
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CH 1 - INTRODUCTION 13
Nucleoside
Nitrogenous Base
Purines
Adenine Adenosine Adenosine monophosphate (Adenylate)
Guanine Guanosine Guanosine monophosphate (Guanylate)
Pyrimidines
Cytosine Cytidine Cytidine monophosphate (Cytidylate)
Thymine Thymidine Thymidine monophosphate (Thymidylate)
Uracil Uridine Uridine monophosphate (Uridylate)
a
The names assume that ribose is the sugar. If the sugar is deoxyribose, then the prefix “deoxy” is added to the name of the nucleo-
side (e.g., deoxyadenosine).
b
The names in parentheses are commonly used to designate the ionized form of the monophosphates. Nucleotides can also be
diphosphates and triphosphates.
(Base + Sugara) Nucleotide (Base + Sugar + Phosphate)
b
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’s
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,10 Lehninger,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’s
resources provide the vast majority of individual pKa values for specific functional groups within the
structures of drug molecules.
2,3
texts and the Wilson and Gisvold4 text are recommended for
2,3
texts, these
REFERENCES
1. Lemke TL, Roche VF, Zito S, eds. Review of Organic Functional Groups. 5th ed. Baltimore, MD:
Wolters Kluwer/Lippincott Williams & Williams; 2011.
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