1. BALANDRIN E T A L .

Plant-Derived Natural Products in Drug Development 7

entities, many other bioactive plant compounds have proven useful as

"leads" or model compounds (templates) for drug syntheses or
semisyntheses {1,2,9,13-20,40-44). Natural compounds of pharmaceutical
importance that were once obtained from higher plant sources, but which
are now produced commercially largely by synthesis, include caffeine,
theophylline, theobromine, ephedrine, pseudoephedrine, emetine,
papaverine, L-dopa, salicylic acid, and A9-tetrahydrocannabinol. In addition,
p-carotene, a plant primary metabolite which may be useful in the prevention
and/or treatment of certain cancers (45; also see chapter by Pezzuto, this
volume), is currently produced synthetically on a commercial scale.
However, despite these numerous examples of economically synthesizable
natural products, it is frequently forgotten that plant secondary compounds
can, and often do, serve additionally as chemical models or templates for
the design and total synthesis of new drug entities. For example, the
belladonna alkaloids (e.g., atropine), physostigmine, quinine, cocaine,
gramine, the opiates (codeine and morphine), papaverine, and salicylic acid
have served as models for the design and synthesis of anticholinergics,
anticholinesterases, antimalarial drugs, benzocaine, procaine, lidocaine
(Xylocaine) and other local anesthetics, the analgesics pentazocine
(Talwin), propoxyphene (Darvon), methadone, and meperidine (Demerol),
verapamil (a near-anagram of the words Papaver and papaverine), and
aspirin (acetylsalicylic acid), respectively (3,42,43,46,47).
Similarly, the study of synthetic analogs of khellin, a furanochromone
derived from the fruits of Ammi visnaga (L.) Lam. and formerly marketed in
the United States as a bronchodilator and coronary medication, led to the
preparation and development of sodium chromoglycate, also known as
chromolyn sodium. Chromolyn is now a major drug used as a
bronchodilator and for its antiallergenic properties. Related synthetic studies
based on the benzofuran moiety eventually led to the development of
amiodarone, which was originally introduced in Europe as a coronary
vasodilator for angina, but which was subsequently found to have a more
useful application in the treatment of a specific type of arrhythmia, the Wolff-
Parkinson-White syndrome, and for arrhythmias resistant to other drugs. It
was introduced as a drug in the U.K. in 1980 and most recently in the United
States {48).
In still another example, the guanidine-type alkaloid, galegine, was
found to be the active principle of goat's rue {Galega officinalis L.), and was
used clinically for the treatment of diabetes. It had been known for some
time previous to this discovery that guanidine itself had antidiabetic
properties, but was too toxic for human use. After hundreds of synthetic
compounds were prepared, metformin, a close relative to galegine, was
developed and marketed as a useful antidiabetic drug {48). These
examples and many others serve to illustrate the continuing value and
importance of plant-derived secondary metabolites as model compounds for
modern drug development.

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8 H U M A N MEDICINAL AGENTS F R O M PLANTS

The Depletion of Genetic Resources and the Urgent Need for

Conservation Efforts

In spite of impressive recent advances in available extraction technology,

separation science (chromatographic techniques), and analytical and
spectroscopic instrumentation, we still know surprisingly little about the
secondary metabolism of most of the world's higher plant species. This is
especially true in the case of tropical rain-forest floras. Although the tropics
contain most of the world's plant species, it has been estimated that more
than half of these are unknown to science (having never been described)
and that most have never been surveyed for chemical constituents (49-56;
also see chapters by Gentry and Soejarto, this volume). For example, it has
been estimated that nothing is known about the chemistry of the vast
majority of the plant species comprising the immense flora of Brazil (53).
The same is probably true of the floras of most of the other countries in
tropical Latin America. This paucity of knowledge is alarming in view of the
current rate of extinction and decimation of tropical floras and ecosystems,
especially forests, before their plants have been adequately catalogued and
studied. If the current trends of destruction of tropical forest habitats and
general global simplification of the biota continue at their present rates,
biochemists, ethnobotanists, molecular biologists, organic chemists,
pharmacognosists, pharmacologists, taxonomists, and other scientists
interested and involved in medicinal plant research may have only a few
decades remaining in which to survey and sample the diverse chemical
constituents of a large part of the plant kingdom for potentially useful novel
bioactive compounds {49-52, 54-57). Under such circumstances, it is
virtually certain that many significant opportunities for successful drug
development will be lost.

Prospects for the Future of Plant-Derived Natural Products in

Drug Discovery and Development

In spite of numerous past successes in the development of plant-derived

drug products, it has been estimated that only 5 to 15% of the ca. 250,000
existing species of higher plants have been systematically surveyed for the
presence of biologically active compounds (14,16,58-61). Moreover, it is
often the case that even plants that are considered to have been
"investigated" have been screened for only a single type (or, at best, a few
types) of biological activity (14). The best example of an extensive, but
narrow, screening program is the National Cancer Institute's search for
antitumor agents from higher plants. Over a 25-year period (1960-1986), an
enormous number of plant extracts representing approximately 35,000 plant
species were tested solely for cytotoxic and/or antitumor activity using only a
few different bioassays (14,37,61-63; also see chapter by Cordell and
coworkers, this volume). The hard-won successes of this massive screening
effort are now apparent in the successful development of anticancer agents

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1. BALANDRIN E T A L . Plant-Derived Natural Products in Drug Development 9

such as taxol and derivatives (see chapter by Kingston, this volume) and
camptothecin and analogs (see chapter by Wall and Wani, this volume).
However, during the course of this screening effort, naturally occurring
compounds potentially useful as new drugs for other ailments or conditions
(e.g., analgesic, antiarthritic, antipsychotic, and psychotropic agents) were
overlooked. Thus, since at least 85% of the world's species of higher plants
have not been adequately surveyed for potentially useful biological activity,
it appears that the plant kingdom has received relatively little attention as a
resource of potentially useful bioactive compounds. Because many plant
secondary metabolites are genus- or species-specific, the chances are
therefore good to excellent that many other plant constituents with potentially
useful biological properties remain undiscovered, uninvestigated, and
undeveloped. Furthermore, there is the hope that in the future, the process
of plant drug discovery and development by way of mass screening will be
greatly facilitated and made more efficient by using new automated multiple
biological screening methods which are now becoming available and which
require only minimal amounts of test samples for evaluation.

Summary and Conclusions

Plant-derived natural products have long been and will continue to be

extremely important as sources of medicinal agents and models for the
design, synthesis, and semisynthesis of novel substances for treating
humankind's diseases. Many of the medicinally important plant-derived
pharmaceuticals have been instrumental and essential in ushering in the
era of modern medicine and therapeutics, and some of these substances,
such as morphine, have attained the official status of strategic materials.
However, despite these many important past contributions from the plant
kingdom, a great many plant species have never been described and
remain unknown to science, and relatively few have been surveyed
systematically to any extent for biologically active chemical constituents.
Thus, it is reasonable to expect that new plant sources of valuable and
pharmaceutical^ interesting materials remain to be discovered and
developed. The continuing interest of at least some sectors of the
pharmaceutical industry in plant-derived drugs is demonstrated by, for
example, the recent investigation by a major pharmaceutical company of a
number of traditional Chinese herbal medicines used to treat cancer,
cardiovascular diseases, and central nervous system disorders (64), and by
a collaborative program instituted by another pharmaceutical giant to
systematically investigate a representative sample of the tropical flora of
Costa Rica. Regrettably, if the current trends of destruction of tropical forests
and general biotic simplification continue at their present rates, scientists
interested and involved in medicinal plant research may have only a few
decades remaining in which to investigate much of the rich diversity of the
plant kingdom for useful new bioactive compounds, and many opportunities
for successful drug development will almost certainly be lost. It is therefore

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10 H U M A N MEDICINAL AGENTS F R O M PLANTS

imperative that endangered, fragile, and over-exploited genetic resources

be preserved to the greatest extent possible for future generations which
may have at their disposal the tools (both technical and intellectual)
necessary to successfully exploit and manage these species more
intelligently.

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