4. Shikimic Acid and Polyketide Derived Natural Products
A
large number of natural products with medicinal uses fall into classes other
than alkaloids and terpenes. Natural products derived from shikimic acid range
in complexity from the very simple, such as vanillin (used primarily as a
flavoring agent), salicylic acid (the precursor of aspirin), lawsone (a
naphthoquinone used in some sunscreens), and scopletin (a coumarin once used as
a uterine sedative), to the more complex, such as the lignan lactone podophyllotoxin. Podophyllotoxin is basically a dimer incorporating two
phenylpropanoid (a nine-carbon unit derived from shikimic acid) units.
Podophyllotoxin was first isolated from Podophyllum peltatum, also known
as mayapple or American mandrake, a plant which has a long history of use as a
cathartic and purgative. Podophyllotoxin has been used to treat warts, and is a
mitotic inhibitor which shows antineoplastic activity. The toxicity of
podophyllotoxin was overcome, in part, by the preparation of derivatives such as
etoposide and teniposide, glucoside derivatives which have a much better profile
of antineoplastic activity. Etoposide, in particular, is used to treat forms of
lung cancer, testicular cancer, and acute lymphocytic leukemia.
Another major biosynthetic pathway to medicinally useful
natural products is the polyketide pathway. These compounds are derived from
poly-
b-keto
chains formed by coupling of acetate or substituted acetate units via
condensation reactions. Among the simplest compounds derived via this pathway
are the fatty acids which make up the essential fats and oils of all living
organisms. A key fatty acid is arachidonic acid. This is the precursor of the prostaglandins, which are involved in a large number of physiological
activities, including smooth muscle contraction and relaxation. Arachidonic acid
is also involved in the production of the thromboxanes, compounds involved in
blood platelet aggregation, and the leukotrienes, compounds involved in allergic
and inflammation processes.
Many of the important polyketides are derived from
microorganisms of various types. For example, erythromycin A is a macrolide
antibiotic produced by Streptomyces erythreus, and is the primary
component of the general antibiotic erythromycin. Erythromycin is used primarily
against Gram-positive bacterial infections, particularly penicillin-resistant
infections. Amphotericin-B is a member of the class of polyene antibiotics. It
is produced by Streptomyces nodosus, and is used primarily as an
antifungal agent. The tetracyclines are broad-spectrum antibiotics produced by
several different Streptomyces species. They have activity against both
Gram-positive and Gram-negative bacteria, although many bacteria have now
developed resistance against them. A very important example of this class,
however, is doxorubicin (also known as adriamycin), which is a widely used
antitumor agent, particularly against solid tumors. Another interesting
polyketide derivative is lovastatin, a compound isolated from Aspergillus
terreus. Lovastatin found wide use as a cholesterol reducing agent (Mevacor®),
although its use has now been supplanted by second generation drugs, such as
simvastatin, and synthetics such as atorvastatin
.
Other important polyketide-derived compounds have been investigated for other
types of medicinal usage. Among these is maytansine, an ansa macrolide isolated
from several Maytenus species of the plant genus Celastraceae.
Demonstrating a broad dose range against the P388 lymphocytic leukemia in mice
at mg/kg
dose levels, maytansine was one of the most promising antineoplastic agents
isolated in the 1970’s, but proved to be too toxic in clinical trials. Severe
toxicity is often found in complex polyketides. The brevetoxins are produced by Gymnodinium
breve (or Ptychodiscus brevis, red tide). These are potent
ichthyotoxins and cause massive fish kills. While they do not appear to cause
significant human toxicity, they can cause irritation of the eyes and throat due
to the aerosol action of the waves in coastal areas. These compounds bind to the
sodium channel and cause persistant activation, increasing sodium ion flux, and
depolarization of excitable cells. Death probably occurs from cardiac and
respiratory paralysis.
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