Chapter 1

Plant-Derived Natural Products

in Drug Discovery and Development
A n Overview
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1 2 2
Manuel F. Balandrin , A. Douglas Kinghorn , and Norman R. Farnsworth
1
NPS Pharmaceuticals, Inc., University of Utah Research Park, Salt
Lake City, UT 84108
Downloaded via 186.154.37.232 on February 5, 2019 at 14:24:11 (UTC).

2
Program for Collaborative Research in the Pharmaceutical Sciences,
College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612

The natural world once served as the source of all medicinal

agents, with higher plants constituting by far the principal
sources of these. Today, higher plants continue to retain
their historical significance as important sources of novel
compounds useful directly as medicinal agents, as model
compounds for synthetic or semisynthetic structure modifi-
cations and optimization, as biochemical and/or pharmaco-
logical probes, and as sources of inspiration for generations
of synthetic organic medicinal chemists. Plant-derived
compounds which have recently undergone development
include the anticancer agents, taxol and camptothecin, the
Chinese antimalarial drug, artemisinin, and the East Indian
Ayurvedic drug, forskolin. These and many other examples
serve to illustrate the continuing value of plant-derived
secondary metabolites as viable compounds for modern
drug development.

Higher plants have served humankind as sources of medicinal agents since

its earliest beginnings. In fact, natural products once served as the source of
all drugs. Today, natural products (and their derivatives and analogs) still
represent over 50% of all drugs in clinical use, with higher plant-derived
natural products representing ca. 25% of the total. On numerous occasions,
the folklore records of many different cultures have provided leads to plants
with useful medicinal properties (1-11). In the past two centuries, the
chemical investigation and purification of extracts of plants purported to have
medicinal properties, and those used as toxins and hunting poisons in their
native habitats, have yielded numerous purified compounds which have

0097-6156/93/0534-0002$06.00/0
© 1993 American Chemical Society

Kinghorn and Balandrin; Human Medicinal Agents from Plants

ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
1. BALANDRIN E T A L . Plant-Derived Natural Products in Drug Development 3

proven to be indispensable in the practice of modern medicine (3,9,12). For

example, the curare alkaloids were obtained from South American vines that
had long been used by natives to make arrow poisons, and African
Strophantus species and Calabar beans yielded medicinally useful cardiac
glycosides and physostigmine, respectively, which were originally used as
arrow and ordeal poisons in their native habitats. The East Indian
snakeroot, Rauvolfia serpentina (L.) Benth. ex Kurz, has been used for
centuries as a native East Indian medicinal plant, and its main active
principle, reserpine, is now used in western medicine as an antihypertensive
and tranquilizer. Similarly, other bioactive and poisonous plants with
extensive folklore histories have yielded the cardiac (Digitalis) glycosides,
AMetrahydrocannabinol, the opiates (codeine, morphine), the Cinchona
alkaloids (quinine, quinidine), the solanaceous tropane alkaloids (atropine,
Ahyoscyamine, scopolamine), pilocarpine, ephedrine, cocaine, theophylline,
vincristine, vinblastine, taxol, and other well-known and useful drugs (3,9-
11).

The Role of Plant-Derived Natural Products in Modern Medicine

The commercial value of drug products still derived directly from higher
plants is considerable and should not be underestimated. For example, in
1980 American consumers paid about $8 billion for prescription drugs
derived solely from higher plant sources (see Table I). From 1959 to 1980,
drugs derived from higher plants represented a constant 25% of all new and
refilled prescriptions dispensed from community pharmacies in the United
States (this does not take into account non-prescription drug products or
drugs used exclusively in hospital settings). Plant-derived drugs thus
represent stable markets upon which both physicians and patients rely. In
addition, worldwide markets in plant-derived drugs are difficult to estimate,
but undoubtedly amount to many additional billions of dollars (13-21).
Some important plant-derived drugs and intermediates that are still obtained
commercially by extraction from their whole-plant sources are listed in Table
I.
Plants continue to be important sources of new drugs, as evidenced
by the recent approvals in the United States of several new plant-derived
drugs, and semi-synthetic and synthetic drugs based on plant secondary
compounds. For example, taxol, an anticancer taxane diterpenoid derived
from the relatively scarce Pacific or western yew tree, Taxus brevifolia Nutt.,
has recently (December, 1992) been approved in the United States for the
treatment of refractory ovarian cancer (see chapter by Kingston, this
volume). Etoposide is a relatively new semisynthetic antineoplastic agent
based on podophyllotoxin, a constituent of the mayapple (also known as
American mandrake), Podophyllum peltatum L , which is useful in the
chemotherapeutic treatment of refractory testicular carcinomas, small cell
lung carcinomas, nonlymphocytic leukemias, and non-Hodgkin's
lymphomas (22-27). Atracurium besylate is a relatively new synthetic

Kinghorn and Balandrin; Human Medicinal Agents from Plants

ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
4 H U M A N MEDICINAL AGENTS F R O M PLANTS

Table I. Some Examples of Economically Important Plant-Derived Drugs

and Intermediates that are Still Obtained Commercially from
Whole-Plant Sources (4,9,13-16,40)

Compound or Class Botanical Sources Therapeutic

Category/Use

A. Steroids

1. Hormones (derived Dioscorea spp. Oral contracep-

from diosgenin, (Mexican yams); tives and other
hecogenin, and soybean-derived steroid drugs
stigmasterol) stigmasterol and hormones

2. Digitalis glycosides Digitalis purpurea L, Cardiotonic

(digoxin, digltoxin) D. lanata Ehrhart glycosides
(foxgloves) (cardenolides)

B. Alkaloids

1. Belladonna-type Atropa belladonna L Anticholinergics

solanaceous
tropane alkaloids
(atropine, Ahyoscy-
amine, scopolamine)
(belladonna), Datura (parasympatho-
metelL, D. stramonium lytics)
L (jimson weed), Hyos-
cyamus niger L (hen-
bane), Mandragora
officinarumL (European
mandrake), and other
solanaceous species

2. Opium alkaloids Papaver somniferum L Analgesics,

(codeine, morphine) (opium poppy) antitussive

3. Reserpine Rauvolfia serpentina Antihypertensive,

(L.) Bentham ex Kurz psychotropic
(East Indian snakeroot)

4. Catharanthus (Vinca) Catharanthus roseus Anticancer

alkaloids (vinblastine, (L) G. Don (Madagas-
vincristine) car! rosy periwinkle)

Kinghorn and Balandrin; Human Medicinal Agents from Plants

ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
1. BALANDRIN E T A L . Plant-Derived Natural Products in Drug Development 5

Table I. Continued

Compound or Class Botanical Sources Therapeutic

Category/Use

5. Physostigmine Physostigma vene- Cholinergic

nosum Balfour (parasympatho-
(Calabar bean) mimetic)

6. Pilocarpine Pilocarpus jaborandi Cholinergic

Holmes (jaborandi) (parasympatho-
and related species mimetic)

7. Cinchona alkaloids Cinchona spp. Antimalarial,

(quinine, quinidine) (Cinchona bark) cardiac antiar-
rhythmic

8. Colchicine Colchicum autumnale L. Antigout

(autumn crocus)

9. Cocaine Erythroxylum coca Local anesthetic

Lamarck (coca leaves)

10. cf-Tubocurarine Strychnos toxifera Skeletal muscle

Bentham, Chondo- relaxant
dendron tomentosum
Ruiz et Pavon (curare)

11. Taxol Taxus brevifolia Nutt. Anticancer

(western or Pacific
yew)

Kinghorn and Balandrin; Human Medicinal Agents from Plants

ACS Symposium Series; American Chemical Society: Washington, DC, 1993.
6 H U M A N MEDICINAL AGENTS F R O M PLANTS

skeletal muscle relaxant which is structurally and pharmacologically related

to the curare alkaloids (26,27). In addition, synthetic A 9 -
tetrahydrocannabinol (originally derived from the marijuana plant, Cannabis
sativa L.) and some of its synthetic analogs (e.g., nabilone) have recently
been approved in the U.S. for the treatment of the nausea associated with
cancer chemotherapy (6,26,28,29). Cannabinoids are also being
developed for use in glaucoma and in neurological disorders (e.g., epilepsy
and dystonia), and as antihypertensives (cardiovascular agents),
antiasthmatics (bronchodilators), and potent analgesics (29).
Plant-derived drugs which are currently undergoing development and
testing include the Chinese drug artemisinin (qinghaosu) and several of its
derivatives, which are newly discovered rapidly acting antimalarial agents
derived from Artemisia annua L (26,30-32; also see chapter by Klayman,
this volume), and forskolin, a naturally occurring labdane diterpene with
antihypertensive, positive inotropic, and adenyl cyclase-activating properties
(33,34; also see chapter by de Souza, this volume). Forskolin is derived
from the root of Coleus forskohlii Briq., a plant used in East Indian folk
medicine and cited in ancient Hindu and Ayurvedic texts (34).
In addition to the compounds mentioned above, other bioactive plant
secondary metabolites are being investigated for their potential utility. For
example, the medicinally active organosulfur compounds of garlic and
onions are currently being investigated and evaluated as potentially useful
cardiovascular agents (35,36; also see chapter by Lawson, this volume),
and ellagic acid, p-carotene, and vitamin E (tocopherols) are being tested
and evaluated for their possible utility as prototype anti-mutagenic and
cancer-preventing agents (26; also see chapter by Pezzuto, this volume).
In the future, advances in our understanding of immunology and
related areas should permit the development of new selective and sensitive
bioassays to guide the isolation of bioactive natural products (37,38). These
continuing developments should provide the means for identifying new
plant-derived antiviral, antitumor, immunostimulating, and adaptogenic
agents (adaptogens reportedly increase stress tolerance) (38). Potential
adaptogenic crude drugs worthy of detailed investigation include American
ginseng (Panax quinquefolius L ) , Asiatic ginseng (Panax ginseng C.A.
Mey), and eleuthero or Siberian ginseng (Eleutherococcus senticosus
Maximowicz) (38,39).

The Role of Plant-Derived Natural Products as Lead Compounds

for the Design, Synthesis, and Development of Novel Drug
Compounds

In addition to the biologically active plant-derived secondary metabolites

(mostly toxins) which have found direct medicinal application as drug

Kinghorn and Balandrin; Human Medicinal Agents from Plants

ACS Symposium Series; American Chemical Society: Washington, DC, 1993.