play a role in connective tissue diseases such as Sjogren’s syndrome and systemic lupus
erythmatosus.
The cytoplasm also contains three classes of cytoplasmic structural proteins: micro-
tubules, microfilaments, and intermediate filaments. Each one of these classes is com-
posed of a host of different proteins: microtubules (tubulin, microtubule-associated
protein [MAP], kinesin, dynein), microfilaments (actin, profilins, moesin, gelsolin,
spectrin, tropomyosin, myosin), and intermediate filament proteins (acidic keratin,
basic keratin, vimentin, desmin, peripherin, nestin). In principle, and increasingly in
practice, each of these proteins could be a target for drug design. Microtubules, for
example, play a role in intracellular transport and the mitotic spindle. Thus, proteins
associated with microtubules are a reasonable target in the design of anti-cancer agents
discussed below.
7.7.1 Targeting Cytoplasmic Structures: MitochondriaMitochondria are energy-producing intracellular organelles. They are thought to have
arisen by the process of endosymbiosisof bacteria; that is to say, since primordial
eukaryotic cells lacked the ability to use oxygen, they benefited when aerobic bacteria
colonized them. Eventually, these bacteria became an integral part of the cell and ulti-
mately evolved into mitochondria. Mitochondria have multiple functions, including
energy production via ATP and the electron-transport chain as well as various bio-
chemical processes (pyruvate oxidation, Krebs cycle, amino acid metabolism). They are
unique in that they are the only organelle, other than the cell nucleus, with their own
DNA. Moreover, the structure of mitochondrial DNA (mtDNA) differs from that of
nuclear DNA. Inherited mitochondrial disorders are transmitted through the maternal
line; the mother transmits her mtDNA through the ovum, but the sperm do not.
The clinical symptoms of mitochondrial diseases are highly varied and include
seizures, vomiting, deafness, dementia, stroke-like episodes, and short stature. Although
there are many types of mitochondrial disorders, four of the most common types are as
follows: Kearns–Sayre syndrome, Leber’s hereditary optic atrophy, MELAS (mitochon-
drialencephalopathy, lactic acidosis and stroke-like episodes) and MERRF (myoclonic
epilepsy with ragged red fibres).
Since mitochondria are essential to cell health, mitochondrial diseases tend to be
severe but, thankfully, relatively uncommon. Accordingly, the medicinal chemistry of
mitochondrial disorders is still in its infancy. There are no truly effective drug therapies
for mitochondrial disorders, but several agents have been reported to be of some bene-
fit in some individuals. These agents include ubiquinone (coenzyme Q10), carnitine,
and riboflavin. These compounds may assist the ailing mitochondria to better complete
their metabolic tasks. However, mitochondrial medicinal chemistry is an area of
research in need of additional attention.
Since mitochondria are energy factories, they are essential to cellular life. This fact
can be usefully exploited in drug design to enable selective killing of unwanted cell types.
For example, the mitochondria of certain parasites are fundamentally different from those
of the host human cells. Accordingly, it is possible to selectively kill such parasites by
targeting the biochemical uniqueness of their mitochondria. Certain 4-hydroxyquinoline
derivatives are effective antiparasitic agents that use this mechanism.
440 MEDICINAL CHEMISTRY