“everyone” with a given disease; pharmacogenomics will enable the tailor-made design
of chemotherapies for specific populations or individuals with diseases.
In attempting to achieve this lofty ideal, pharmacogenomics will rely upon genetic
data such as single nucleotide polymorphism maps. The assembly of a single nucleotide
polymorphism (SNP) map for the genome will represent a set of characterized bio-
markers spread throughout the human genome; this SNP map will highlight individual
variations within particular genes, some of which may be associated with particular dis-
eases, thus identifying the genetic variability inherent in human populations that is cru-
cial to the task of individualized drug design.
The emergence of pharmacogenomics will also enhance the interaction of medicinal
chemistry as a discipline with other disciplines, including the social sciences, ethics,
and economics. Society has a difficult enough time paying for currently available drug
therapies. Who will pay for individualized therapies? Will this further widen the chasm
between “have” and “have-not” populations, between “developed” and “developing”
nations?
3.3 SYNTHESIS OF A LEAD COMPOUND
Although drug design and computer-aided molecular design are powerful techniques,
ultimately the lead compound must be made and evaluated; it is imperative that we
make the jump from in silico toin vitro andin vivo. This is the point at which medici-
nal chemistry overlaps heavily with synthetic organic chemistry. Organic synthesis
(from the Greek, synthetikos, “to put together”) is the preparation of complicated
organic molecules from other, simpler, organic compounds. Because of the ability of
carbon atoms to form chains, multiple bonds, and rings, an almost unimaginably large
number of organic compounds can be conceived and created.
In planning a synthetic route for the preparation of a desired molecule (termed the
target molecule) the organic chemist devises a synthetic tree–an outline of multiple
available routes to get to the target molecule from available starting materials. An
organic synthesis may be either linearorconvergent. A linear synthesis constructs the
target molecule from a single starting material and progresses in a sequential step-by-
step fashion. A convergent synthesis creates multiple subunits through several parallel
linear syntheses, and then assembles the subunits in a single final step. Since overall
yield is a function of the number of steps performed, convergent syntheses have higher
yields and are preferred over linear syntheses.
In creating synthetic routes for the development of drug molecules, the synthetic
chemist wants to create a molecular entity in which functional groups (carbonyls,
amines, etc.) are correctly positioned in three-dimensional space; this will enable the
creation of functional biophoric fragments such as the pharmacophore. The synthetic
chemist has ten general classes of reactions available for such synthetic tasks:
- Aliphatic nucleophilic substitution
- Aromatic electrophilic substitution
- Aliphatic electrophilic substitution
- Aromatic nucleophilic substitution
- Free-radical substitution
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