Medicinal Chemistry

a variety of analogs have been prepared and evaluated. Ribozyme-based drugs may in
theory be used against a diversity of disorders, including cancer and viral infections.

8.4.2 Antisense Oligonucleotides as Potential Therapeutics

Synthetic oligonucleotide ligands, designed to bind to RNA receptors in a sequence-
specific fashion by Watson–Crick base pair recognition, are another nucleotide-based
emerging drug discovery paradigm. This approach to the discovery of drug design leads
is called the antisense technology. More than 20 oligonucleotides with anti-inflammatory,
antineoplastic, and antiviral properties have been preliminarily evaluated in human
clinical trials. Many of these are full-length compounds ranging from 15 to 20 bases.
However, bioisosteric equivalents are frequently needed to ensure survivability within
the biological milieu. The first generation of antisense oligonucleotides were phospho-
rothioate oligodeoxynucleotides (PSs). Second-generation antisense oligonucleotides
have incorporated 2′-O-methyl and 2′-O-methoxyethyl modifications.

8.5 Lipids as Drugs and Drug Design Targets

In 1934, von Euler in Sweden discovered a group of polyunsaturated fatty acids that had
a powerful effect on smooth muscle and blood pressure. They were isolated from sem-
inal fluid and the prostate, and were named prostaglandins. Their structure was eluci-
dated by the Samuelsson group in Stockholm, who, in 1975, also discovered even more
potent fatty acid metabolites, the thromboxanesandprostacyclin. The effect of these
compounds on blood platelet aggregation and the contraction of blood vessels con-
nected them to the etiology of stroke and cardiovascular disease. Additionally, it was
discovered that both steroidal and nonsteroidal anti-inflammatory agents act through the
prostaglandin system, adding further impetus to the research in this area. Consequently,
the field of bioactive lipids became a center of intense interest.
As the research area expanded, the leukotrieneswere discovered next. The leukotrienes
are potent lipid mediators associated with asthma and allergic reactions. In contrast to
prostaglandins, leukotrienes are made predominantly in inflammatory cells, like leuko-
cytes, macrophages, and mast cells.
Prostaglandins, thromboxane, and the leukotrienes are lipids that are collectively
calledeicosanoids,since they are all derived from the C20 fatty acid, arachidonic acid
[eicosa(Gr.) =twenty]. Over the past twenty years, the eicosanoids have emerged as
important molecules around which to target drug design and development.

ENDOGENOUS MACROMOLECULES 519

Figure 8.8 Locations of strategic modification positions for drug design in ribonucleotides.