Lipophilic groups that are not easily hydrolyzed are used extensively for depot
preparations, which liberate the active drug molecule slowly, for a period of days or
weeks. Steroid hormone palmitates and pamoates, and antimalarial esters (e.g., cycloguanil
pamoate,3.29), can deliver the active drugs over a prolonged time; cycloguanil, for
example, is released over a period of several months. This can be a great convenience
for the patient, especially in areas with remote medical facilities.
Drug designers have attempted for many years to use selective drug-transport moi-
eties, and have met with moderate success. The idea is to attach a drug, such as an anti-
tumor agent, to a natural product that will accumulate selectively in a specific organ
and act as a “Trojan horse” for the drug. The attachment of alkylating agents to estro-
gens has been tried in the treatment of ovarian cancer, and amino acids have also been
used as drug carriers. A recent ingenious application of the carrier concept is the uti-
lization of antibodies— which can, at least in principle, be tailored to any site — as
drug carriers. In this regard, antitumor agents such as adriamycin (3.30) and
methotrexate (3.31) have been linked covalently to leukemia antibodies and melanoma
antibodies, with some initial success. The large-scale preparation of antibodies is, of
course, a major difficulty in this approach; however, the new monoclonal antibodies
hold great promise.
3.5.3.3 Masking of Side Effects or Toxicity
Masking of the side effects or toxicity of drugs was historically the first application of
the prodrug concept. This concept goes back to the turn of the twentieth century, and in
fact many prodrugs were not at the time really recognized as such. For instance, castor
oil is a laxative because it is hydrolyzed intestinally to the active ricinoleic acid.
However, the classical example is prontosil (3.32), which undergoes a reduction to sul-
fanilamide. The analgesic phenacetin (3.33) acts in the form of its hydrolysis product,
DESIGNING DRUG MOLECULES TO FIT RECEPTORS 157