Medicinal Chemistry

agent. Analogs of purines and pyrimidines have been used for other applications as well.
For example, analogs of uracil have been studied as sedatives and as anxiolytics(drugs
to treat anxiety). The strengths and weaknesses of such a design approach are apparent.
Analogs of purines or pyrimidines will have predictable pharmacokinetic properties;
however, they may also have undesirable pharmacodynamic properties,being carcinogenic,
mutagenic, or teratogenic by interfering with endogenous nucleic acids.

8.4.1 Ribozymes as Drug Design Targets

There are other ways in which nucleic-acid-related compounds could be exploited
as therapeutics. A new, emerging area concerns the application of RNA as a drug. The dis-
covery of catalytic RNA (ribozymes) by Cech and Altman was a fundamental advance in
nucleic acid chemistry. According to traditional “double helix dogma,” RNA was a passive
information-transmitting molecule. The identification of ribozymes enabled the conceptual
advance that RNA can also act as a catalyst for the following biochemical processes:

1. RNA splicing


2. RNA cleavage


3. DNA cleavage


4. Peptide bond cleavage


5. Transfer of phosphate groups

Ribozymes therefore show promise as therapeutic agents with which to downregulate
RNA activity. For instance, a ribozyme-based drug could be used to attack the mRNA
coding for a protein associated with a particular disease; this attack would prevent the
protein’s expression by rendering the mRNA untranslatable.
Engineering drugs on the basis of RNA is beset with the same problems as engi-
neering drugs on the basis of peptides. Unmodified RNA is metabolically vulnerable
and unstable within a biological milieu. Therefore, just as there is peptidomimetic
chemistry to make peptide-like drugs to mimic peptides, so too is “nucleotidomimetic”
chemistry beginning to emerge. There are seven obvious positions at which to modify
a nucleotide in order to make it more “drug-like” and less “nucleotide-like”:

1. 2′Sugar position


2. 3′Sugar position


3. 4′Sugar position


4. 5′Sugar position


5. Replacing the base with base bioisosteres


6. Replacing the phosphodiester backbone with bioisosteres


7. Using non-nucleotide linkers between nucleotides

There are many examples of each of these possibilities (see figure 8.8). In the case of
the 2′sugar position, most of the 2′-substititutions have been achieved with 2′-O-alkyl,
2 ′-amino, and 2′-fluoro replacements. Purine base substitutions have been performed
with 2-aminopurine, xanthosine, and isoguanosine. Phosphodiester replacements have
been effected using phosphorothioate substitutions. As for the non-nucleotide linkers,
propanediol linkers have been employed. Using these various bioisosteric substitutions,

518 MEDICINAL CHEMISTRY