Chemistry Reference
In-Depth Information
of the series is nodulisporic acid A (
119
), which selectively modulates the activity
of insect-specific glutamate-gated chloride channels (153).
12.13 PHARMACEUTICAL MODELS
The roles played by natural products as models for design and development of
pharmaceutical agents are too many to cover in this overview. A few examples are
illustrated during the discussions of specific disease areas above. For example,
a marine sponge-derived nucleoside was the precursor for various nucleoside-
based antiviral agents, pepstatin for renin and HIV protease inhibitors, snake
venom peptide for ACE inhibitors, lovastatin and compactin for all statins, and
ephedrine for many painkillers and
-blockers. Below are a few critical examples
that have played a big role in defining leads for some therapeutic areas but have
not resulted in a drug yet.
Asperlicin (
120
) was isolated from
Aspergillus alliaceus
as a weak cholecys-
tokinin A receptor (CCK-A) antagonist by using CCK receptor binding screening
assays (154). It is a competitive antagonist of CCK-A (but not CCK-B) but did
not have sufficient potency or oral activity to qualify as a drug candidate. In a
remarkable strategy, medicinal chemists simplified the molecule to a benzodi-
azepine core of asperlicin, which led to the synthesis of potent, safe, and orally
active analogs (
121
and
122
) with selectivity for either CCK-A (
121
) or CCK-B
(
122
) receptors. They entered human clinical trials but were abandoned because
of lack of efficacy (155, 156). The benzodiazepine scaffold was coined as “privi-
leged structures” by Evans et al (155). This discovery is a beautiful demonstration
of how a natural product became a model for the CCK program and played a
pivotal role in defining the entire field (138).
The second example is apicidin (
123
), which is a cyclic tetrapeptide isolated
from a fungus
Fusarium pallidoroseum
by using an empiric antiprotozoal screen
(157, 158). It showed potent inhibition of apicomplexan protozoa including the
malarial parasite
Plasmodium falciparum
and coccidiosis parasite
Eimeria
spp.
It was effective
in vivo
against reducing malaria parasite infection in a mouse
model (157) and exhibited strong activity against tumor cell lines (159, 160).
Cyclic tetrapeptides with a terminal epoxy-ketone were known to be effective
cytotoxic agents before the discovery of apicidin, but the pharmacophore was
associated with the epoxy-ketone group (e.g., Trapoxin B,
124
) with covalent
β
O
OH
NH
O
O
N
N
N
N
N
H
N
N
H
N
N
N
O
O
O
O
Asperlicin (
120
)
MK-329(
121
)
L-365,260 (
122
)
