Medicinal Chemistry

from one of the procaspase units of the homodimer, and a small unit from the other
procaspase.
The activated caspases kill cells by a process of selectively directed proteolysis. The
caspases catalyze the cleavage and breakdown of a select group of proteins within the
cell. This highly focused cellular destruction produces a disassembly of the cell into
membrane-limited fragments called apoptotic bodies. These bodies are engulfed and
digested within phagocytes. The entire process is focused and tightly controlled, pre-
venting the release of protein breakdown products into the surrounding environment;
in turn, this precludes the activation of an inflammatory response.
Small-molecule inhibitors of caspases would have obvious use as therapeutics. The
current medicinal chemistry research literature is rich in studies attempting to achieve
this important design goal. In early work, both reversible and irreversible peptide-based
inhibitors of various caspases have been developed. Peptidomimetic ketones were also
devised; for example, acyloxymethyl ketones were designed and developed as potent,
time-dependent irreversible caspase inhibitors.

8.2.8 Enzyme Cofactors as Targets in Drug Design: Vitamins

Vitamins are low-molecular-weight organic compounds that, in almost all cases, function
ascoenzymes—that is, molecules that “assist” an enzyme in the completion of its catalytic
task. As such, they are indispensable in a multitude of biochemical reactions; however,
higher organisms cannot biosynthesize many of them. Those that must be supplied in the
human diet are classified in the vitamin category because their absence leads to deficiency
diseases. Vitamins therefore have therapeutic importance; hence they are of interest to the
medicinal chemist, even though they belong to a mature and slow-moving field.
The knowledge of some vitamins reaches back into folk medicine: North American
aboriginal peoples treated scurvy (later recognized as vitamin C deficiency) with cedar
leaf tea (Thuja), and, from the seventeenth century on, the British Navy issued lime

ENDOGENOUS MACROMOLECULES 503

Table 8.2 Continued

Caspace Alternate nonmenclature Function Substrates

Caspase-9 Apaf-3, ICE-LAP6, Mch6 Apoptosis Caspase-3
Caspase-7
PARP
pro-Caspase-9
Caspase-10 FLICE-2, Mch4 Apoptosis Caspase-3
Caspase-4
Caspase-6
Caspase-7
Caspase-8
Caspase-9
Caspase-11 Ich_3, ICE-B Inflammation and apoptosis
Caspase-12 ICE_C Apoptosis
Caspase-13 ERICE Inflammation