394 MEDICINAL CHEMISTRY
Unlike these nonspecific agents, mycophenolate mofetil (6.4) tends to be a lymphocyte-
specific cytotoxic agent. Mycophenolate mofetil is a semisynthetic derivative of mycophe-
nolicacid, isolated from the mold Penicillium glaucum.It inhibits both T and B
lymphocyte action. Since it inhibits the enzyme inosine monophosphate dehydroge-
nase, which catalyses purine synthesis in lymphocytes, this agent has a more specific
effect on lymphocytes than on other cell types. Mizoribine (6.5) is a closely related drug
which inhibits nucleotide synthesis, preferentially in lymphocytes.
The next major class of immunosuppressive agents is the corticosteroids, which
includes drugs such as prednisone (3.7) and dexamethasone (5.65). Corticosteroids
affect immune function through many different mechanisms. They interfere with the cell
cycle of lymphoid cells and are even toxic to specific subsets of T cells. Corticosteroids
impair the process of chemotaxis, decrease the number of circulating lymphocytes, and
partially inhibit IL-1, IL-2, and INF-γproduction. Additionally, corticosteroids lower the
concentrations of specific immunoglobulins. Because of this broad spectrum of activity,
corticosteroids are the most widely used immunosuppressive agents. Regrettably, corti-
costeroids are also hormones and thus their use is associated with significant and poten-
tially severe side effects. Long-term use of corticosteroids results in a distinctive cluster
of side effects known as Cushing’s syndrome.To avoid these side effects, the cytotoxic
agents, such as azathioprine and cyclophosphamide, are occasionally used; accordingly,
the cytotoxic agents are sometimes referred to as steroid sparing agents.
In addition to steroids, a structurally diverse group of natural products is used to
inhibit cytokine production and action. The first of these is cyclosporine (6.6).
Cyclosporine is an antibiotic polypeptide isolated from fungi. It influences immune
function through several routes. Following administration, cyclosporine is taken up by
lymphocytes and binds to a receptor protein, called cyclophilin, located in the cyto-
plasm of the lymphocyte. By interacting with this cytoplasmic protein, cyclosporine
inhibits the enzyme phosphatase calcineurin, which in turn plays an integral role in
T-cell signal transduction. Cyclosporine also inhibits the gene transcription of IL-2,
IL-3, IFN-γ, and other cytokines produced by activated T cells.