Chemistry Reference
In-Depth Information
that several authors have gone on record as advocating an increase in the drug
discovery effort assigned to natural products (4, 6, 7).
This review summarizes the contributions of natural products to the discovery
and development of anticancer agents. It includes information on many natural
products and natural product analogs that are in clinical use as anticancer drugs,
and it describes some natural product drugs in late-stage clinical trials. Because
of space limitations, it is does not provide a comprehensive listing of all natural
product and natural product-derived anticancer agents; readers interested in such
a listing should consult a recent review (8).
13.1 OVERVIEW OF NATURAL PRODUCTS
AS ANTICANCER AGENTS
As of the time of writing, 178 drugs are approved world-wide for the treatment
of cancer in all of its manifestations, and 175 of these are listed together with
their classifications as to source in a recent review (8). Of the 178 approved
antitumor agents, 25 (14%) are natural products, 48 (27%) are modified natural
products, and 20 (11%) are synthetic compounds derived from a natural product
pharmacophore. Natural products have thus led to 52% of the approved drugs
against the collection of diseases that go by the collective name of cancer. Another
20 drugs (11%) are biologics, with the remainder being synthetic compounds. The
highly significant contribution of natural products to anticancer drug discovery
is clear from these figures.
The term “natural product” describes a broad class of anticancer agents, which
range from complex compounds like paclitaxel and vinblastine to relatively
simple compounds such as combretastatin-A4. Associated with these different
structures are several different mechanisms of action, some of which were only
discovered when the corresponding natural product was investigated. The fol-
lowing sections are divided on the basis of the mechanism of action of the drugs
rather than their source, and consequently, any given section may include plant,
microbial, or marine-derived agents. The broadest division is between those com-
pounds that act by targeting proteins in some way and those compounds that act
by direct interactions with DNA or RNA. Thus, these two broad areas provide
the two major sections of this review.
13.2 COMPOUNDS THAT TARGET PROTEINS
The mammalian cell cycle is a complex and carefully regulated biologic process
that leads to cell division, and faulty regulation of this cycle is one feature of most
cancers. The cell cycle thus offers several targets for therapeutic intervention, and
several of the proteins involved either directly or indirectly in controlling this
cycle are the targets of some important anticancer agents. The most important
targets, in terms of the number of drugs that target them, are the proteins tubulin,
topoisomerase I, and topoisomerase II, but other proteins such as the checkpoint
