FUNCTIONAL GROUP MODIFICATION

ISOSTERISM AND BIOISOSTERISM

When a lead compound is first discovered for a particular disease state, it

often lacks the required potency and pharmacokinetic properties, suitable for
making it a viable clinical candidate. These may include undesirable side effects,
physicochemical properties that limit bioavailability, and adverse metabolic or
excretion properties. These undesirable properties could be due to specific
functional groups present in the molecule. The medicinal chemist therefore must
modify the compound to reduce or eliminate these undesirable features without
losing the desired biological activity. Replacement or modification of functional
groups with other groups having similar properties is known as isosteric or
bioisosteric replacement.

Isosterism
In 1919, Langmuir first developed the concept of chemical isosterism to
describe the similarities in physical properties among atoms, functional groups,
radicals, and molecules. The similarities among atoms described by Langmuir
primarily resulted from the fact that these atoms contained the same number of
valence electrons and came from the same columns within the periodic table. This
concept was limited to elements in adjacent rows and columns, inorganic
molecules, ions and small organic molecules such as diazomethane and ketene. The
table below shows a comparison of the physical properties of N2O and CO2 to
illustrate Langmuir's concept.

To account for similarities between groups with the same number of valence
electrons but different numbers of atoms, Grimm developed his hydride
displacement law. However, this is not a "law" in the strict sense, but more of an
illustration of similar physical properties among closely related functional groups.
The table below presents an example of hydride displacement.

Descending diagonally from left to right in the table H atoms are progressively
added to maintain the same number of valence electrons for each group of atoms
within a column. Within each column the groups are considered to be "pseudo
atoms" with respect to one another. Thus, NH2 is considered to be isosteric to OH,
etc.
This early view of isosterism did not consider the actual location, motion,
and resonance of electrons within the orbitals of these functional group
replacements. Careful observation of this table reveals that some groups do share
similar physical and chemical properties, but others have very different properties
despite having the same number of valence electrons. For example, OH and NH2
do share similar hydrogen bonding properties and should therefore be
interchangeable if that is the only criterion necessary. But, the NH2 is basic
whereas the OH is neutral. Hence, at physiological pH the NH2 group would impart
a positive charge to the molecule. If OH is being substituted by NH2 the additional
positive charge could have a significant effect on the overall physico-chemical
properties of the molecule in which it is being introduced. The difference in
physico-chemical properties of the CH3 group relative to the OH and NH2 groups is
even greater. In addition to basicity and acidity, this "law" fails to take into account
other important physical chemical parameters such as electronegativity,
polarizability, bond angles, size, shape of molecular orbitals, electron density, and
partition coefficients, all of which contribute significantly to the overall
physicochemical properties of a molecule.

Instead of considering only partial structures Hinsberg applied the concept of

isosterism to entire molecules. He developed the concept of "ring equivalents";
groups that can be exchanged for one another in aromatic ring systems without
drastic changes in physico-chemical properties relative to the parent structure.
Benzene, thiophene and pyridine illustrate this concept (see figure below).

A -CH=CH- group in benzene is replaced by the divalent sulfur, -S-, in thiophene,

and a -CH= is replaced by the trivalent -N = to give pyridine. The physical
properties of benzene and thiophene are very similar. For example, the boiling
point of benzene is 81.1C and that of thiophene is 84.4C (at 760 mm Hg).
Pyridine, however, deviates with a boiling point of 115-116C. Hinsberg therefore
concluded that divalent sulfur (-S- or thioether) must resemble -C=C- in shape and
these groups were considered to be isosteric. Note that hydrogen atoms are ignored
in this comparison. Today this isosteric relationship is seen in many drugs.

Bioisosterism
It is difficult to relate biological properties to physicochemical properties of
individual atoms, functional groups or entire molecules because many physical and
chemical parameters are involved simultaneously and are therefore difficult to
quantitate. Simple relationships as described above often do not hold up across the
many types of biological systems seen with medicinal agents. That is, what may
work as an isosteric replacement in one biological system (or a given drug
receptor) may not in another. Because of this, it was necessary to introduce the
term "bioisosterism" to describe functional groups related in structure and having
similar biologica effects. Friedman introduced the term bioisosterism and defined it

as: "Bioisosteres are (functional) groups or molecules that have chemical and
physical similarities producing broadly similar biological properties." Recently
Burger expanded this definition to take into account biochemical views of
biological activity: "Bioisosteres are compounds or groups that possess nearly
equal molecular shapes and volumes, approximately the same distribution of
electrons, and which exhibit similar physical properties such as hydrophobicity.
Bioisosteric compounds affect the same biochemically associated systems as
agonist or antagonists and thereby produce biological properties that are related to
each other." The key point is that the same pharmacologic target is influenced by
bioisoteres as agonists or antagonists. What may work as a bioisosteric group in
one biological system (or receptor) may not have similar effects on another.

Classical and Nonclassical Bioisosteres

Bioisosteric groups can be subdivided into two categories: Classical and
nonclassical bioisosteres. Functional groups that satisfy the original conditions of
Langmuir and Grimm are referred to as classical bioisosteres. Nonclassical
bioisosteres do not obey steric and electronic definitions of classical bioisoteres
and do not necessarily have the same number of atoms as the substituent they
replace. A wider set of compounds and functional groups are encompassed by
nonclassical bioisoteres which produce, at the molecular level, qualitatively similar
agonist or antagonist responses. In animals, many hormones, neurotransmitters etc.
with very similar structures and biological actions can be classified as bioisosteres.
An example would be the insulins isolated from various mammalian species. Even
though these insulins may differ by several amino acid residues, they still produce
the same biological effects. If this did not occur, the use of insulin to treat diabetes
would have had to wait another 60 years for recombinant DNA technology to allow
production of human insulin.
What maybe a successful bioisosteric replacement for a given molecule
interacting with a particular receptor in one instance quite often has no activity, or
abolishes biologica activity in another system. Thus, the use of bioisosteric
replacement (classical or nonclassical) in drug design is highly dependent upon the
biological system being investigated. No hard and fast rules exist to determine

what bioisosteric replacement is going to work with a given molecule, although as

the following tables and examples demonstrate, some generalizations have been
possible. However, the medicinal chemist still must rely on experience and
intuition in order to decide the best approach to be used when applying this
strategy.

Classical bioisosteres can be further subdivided as shown below, and examples are
provided in the Table that follows
A.

Monovalent atoms and groups

B.

Divalent atoms and groups

C.

~rivalent atoms and groups

D.

Tetrasubstituted atoms

E.

Ring equivalents

Substitution of hydrogen by fluorine is one of the most common monovalent

isosteric replacements. Sterically hydrogen and fluorine are quite similar with their
van der Waal's radii being 1.2 and 1.35 A, respectively. Since fluorine is the most
electronegative element in the periodic table, any differences in biological activity
resulting from replacement of hydrogen with fluorine can be attributed to this
property. A classical example of hydrogen replacement by fluorine is development
of the antineoplastic agent 5-fluorouracil from uracil.

Uracil

5-fluorouracil

Another example is shown in the figure below where the chlorine of

chlorothiazide has been replaced with bromine and a trifluoromethyl group. For
each of the substitutions the electronic () and hydrophobic () properties of each
group are maintained relatively constant while the size of each group varies
significantly as indicated by the Taft steric parameter (Es).

The figure below shows an example of classical isosteric substitution of an

amino for hydroxyl group in folic acid. The amino group is capable of mimicking
the tautomeric forms of folic acid and providing the appropriate hydrogen bonds to
the enzyme active site.

A tetravalent bioisosteric replacement study was done by Grisar et al. with a

series of -tocopherol analogues (see figure below). -Tocopherol has been shown
to scavenge lipoperoxyl and superoxide radicals and to accumulate in heart tissue.
This is thought to be part of its mechanism of action for reducing cardiac damage
due to myocardial infarction. All of the bioisosteric analogues were found to
produce similar biological activity.