Figure 30.1
The antibiotic netropsin (turquoise
atoms) bound in the minor groove
of DNA.Section 30.11 Combinatorial Organic Synthesis 1223donating ability of the substituent. When, however, another QSAR analysis showed
that the toxicity of these compounds was also related to the electron-donating ability
of the substituent, it was decided that it would be fruitless to continue synthesizing and
testing this class of compounds.
In addition to solubility and substituent parameters, some of the properties that
have been correlated with biological activity are oxidation–reduction potential, molec-
ular size, interatomic distance between functional groups, degree of ionization, and
configuration.30.10 Molecular Modeling
Because the shape of a molecule determines whether it will be recognized by a recep-
tor and, therefore, whether it will exhibit biological activity, compounds with similar
biological activity often have similar structures. Because computers can draw molecu-
lar models of compounds on a video display and move them around to assume differ-
ent conformations, computer molecular modelingallows more rational drug design.
There are computer programs that allow chemists to scan existing collections of thou-
sands of compounds to find those with appropriate structural and conformational
properties.
Any compound that shows promise can be drawn on a computer display, along with
the three-dimensional image of a receptor site. For example, the binding of netropsin,
an antibiotic with a wide range of antimicrobial activity, to the minor groove of DNA
is shown in Figure 30.1.
The fit between the compound and the receptor may suggest modifications that can
be made to the compound that result in more favorable binding. In this way, the selec-
tion of compounds to be synthesized for the purpose of screening for biological activ-
ity can be more rational and will allow pharmacologically active compounds to be
discovered more rapidly. The technique will become more valuable as scientists learn
more about receptor sites.30.11 Combinatorial Organic Synthesis
The need for large collections of compounds that can be screened for biological activ-
ity in the constant search for new drugs has led organic chemists to a synthetic strate-
gy that employs the concept of mass production. This strategy, called combinatorial
organic synthesis, involves the synthesis of a large group of related compounds—
known as a library—by covalently connecting sets of building blocks of various struc-
tures. For example, if a compound can be synthesized by connecting three different
building blocks, and if each set of building blocks contains 10 interchangeable com-
pounds, then 1000 different compounds can be prepared. This ap-
proach clearly mimics nature, which uses amino acids and nucleic acids as building
blocks to synthesize an enormous number of different proteins and nucleic acids.
The first requirement in combinatorial synthesis is the availability of an assortment
of reactive small molecules to be used as building blocks. Because of the ready avail-
ability of amino acids, combinatorial synthesis made its first appearance in the cre-
ation of peptide libraries. Peptides, however, have limited use as therapeutic agents
because they generally cannot be taken orally and are rapidly metabolized. Currently,
organic chemists create libraries of small organic molecules for use in a combinatorial
approach for modifying lead compoundsor as a complement to rational drug design.
An example of the approach used in combinatorial synthesis is the creation of a li-
brary of benzodiazepines. These compounds can be thought of as originating from
three different sets of building blocks: a substituted 2-aminobenzophenone, an amino
acid, and an alkylating agent.110 * 10 * 102BRUI30-1204_ 1228r2 18-03-2003 8:55 AM Page 1223