Industrial Strategies for the Discovery of

Bioactive Compounds from Plants

• There are in principle two approaches for drug discovery from plant sources:

(1) sourcing using various strategies followed by "random" screening

(2) use of information from traditional medicine on biologically active plant extracts and isolation of the active secondary product(s).

• The source country should be involved in the discovery process and should benefit by technology transfer and commercial rights to novel products.

1. Use of information from traditional medicine, the most used or widely used strategy.

2. Sourcing from extreme and/or as yet untouched ecosystems.

3. Ecological observations. For example, individual plant species or lines not attacked by certain diseases may contain fungicidal compounds.

4. Chemotaxonomy, which is particularly useful for discovering species with a higher yield or modified lead structures.

5. Use of biologically activated plants, e.g., after infection, infestation by insects, or under extreme environmental conditions.

6. Use of cell cultures with different growth conditions and/or induction by microbial elicitors.

• This technology, which offers great commercial potential, is currently used by some specialized companies (see, e.g., www.phytera.com).

• In principle, two different approaches are applied today:

1. The traditional approach of using crude extracts followed by purification of active principles after the discovery of activity in a particular screening system.

2. The alternative approach, which first separates the constituents of a plant extract and then applies such more or less pure products to the screening process.

• In order to be successful in using plant secondary products in an industrial discovery process, several approaches are possible:

1. Generation of a large number of extracts obtained under reproducible conditions and from diverse and reliable sources in a factory-like setup.

2. Generation of a large number of diverse pure natural products that can be submitted to the standard screening procedures.

3. Further development of on-line separation, screening, and structural elucidation.

The Use of Selected Medicinal Herbs for Chemoprevention and

Treatment of Cancer, Parkinson’s Disease, Heart Disease, and

Depression

Cancer

• Evidence from tissue culture, animal models, and human studies suggests that flavonoid-rich fruits, in particular, deeply colored berries(التوت), have promise to limit the development and severity of diseases based on inflammatory processes including atherosclerosis and ischemic stroke, neurodegenerative diseases of aging, and certain cancers.

• The first report of the anticancer properties of “anthocyan” flavonoids from fruits and vegetables was published over 40 years ago and cited their significance as cell respiratory activators for cancer prophylaxis and therapy.

Case Study on and Cancer• The anticancer effects of berries are mediated

through many mechanisms mostly associated with their flavonoid content.

• Although berries from numerous families and included genera provide an array of flavonoid compounds that could contribute to cancer chemoprevention and therapy, species from the family Ericaceae, and especially the genus Vaccinium, are widely favored for their anticancer attributes.

• Although little direct data uniquely link berry consumption with lower cancer risk, evidence is mounting that berry extracts and berry phytochemicals modulate biomarkers of DNA damage and indicators of malignant transformation in vitro and in vivo.

• The anticancer effects on macromolecules, in particular DNA, and cells, tissues, and organ systems involve

(1) protection from genotoxicity; (2) regulation of carcinogen and xenobiotic

metabolizing enzymes; (3) ability to prevent and mitigate damage resulting

from oxidative stress;

(4) inhibition of cancer cell proliferation and induction of apoptosis;

(5) Regulation of subcellular signaling pathways and modulation of transcription factors; and

(6) inhibition of growth factors and inflammatory cytokines linked to tumor angiogenesis and invasiveness.

• In addition, berry phytochemicals may induce sensitivity of tumor cells to chemotherapeutic agents by inhibiting pathways that lead to drug resistance and ameliorate therapy-associated toxicities.

Conclusions• Results show promise for the cancer

chemopreventive and possible therapeutic applications of Vaccinium preparations and derived phenolic acids, anthocyanins, catechins, stilbenes, and several other flavonoids.

• Although most of the work done to date indicates a chemopreventive activity of these compounds, there are some studies that show cancer-inducing or no effects.

• Vaccinium flavonoids have demonstrated other mechanisms for anti-aging and anticancer potential.

• Several common mechanisms by which these chemicals exert their effects appear to be conducive to additive, synergistic, or antagonistic interactions.

Parkinson’s Disease

• Parkinson’s disease is a degenerative disorder of the central nervous system that often impairs the sufferer’s motor skills and speech.

• So far, there have been no known human clinical trials conducted that attempt to unambiguously answer the question: Do blueberries in the diet have any positive benefits for patients afflicted with early stages of Parkinson’s disease?

• This is remarkable in light of the fact that manifold studies conducted by many researchers using a rat model system, have shown how a blueberry-rich diet, elicits significant improvement in motor skills and cognitive ability in rats induced to manifest PD symptoms.

• What is the basis for blueberries having beneficial effects for PD, aside from their nutritional value? Blueberries contain an array of anthocyanins and polyphenols which have high antioxidant activity and anti-inflammatory activity.

• It is possible that these kinds of constituents act synergistically at target sites of action .

• However, no one yet knows how blueberries act at target sites in the human brain to ameliorate the severe deleterious effects of PD on cognitive ability and motor skills.

• Vaccinium myrtillus preparations are documented for their anthocyanin content and improvement of cerebral functions, neurotransmitter levels, emotional stress, and progression of neurodegenerative conditions such as Parkinson’s and Alzheimer’s diseases.

Heart Disease

• Digoxin is one of the most commonly prescribed cardiac glycosides by physicians, a closely related group of drugs that can affect the myocardium or heart muscle.

• The term “digitalis” is used to describe the entire group of cardiac glycosides.

• Digitalis is more commonly prescribed as digoxin, tradename LanoxinTM, an extract from the leaves of Digitalis lanata Ehrh., or sometimes as digitoxin, from foxglove or the leaves of Digitalis purpurea L.

Heart Failure• Heart failure is state in which an abnormality of

cardiac muscle function results in the failure of the heart to pump blood out to the body at a rate commensurate with its metabolic requirements.

Atrial Fibrillation• Atrial fibrillation, a type of heart arrhythmia

defined as an irregular heart beat or loss of rhythm is a common heart arrhythmia that can occur with or without heart failure.

• Atrial fibrillation, often describing the heart as a bag of worms, begins as a loss of atrial contraction, irregular rhythm, and increased heart rate leading to a decreased cardiac output.

The Evidence for Heart Failure• Digoxin is widely used to treat mild-to-moderate

heart failure in normal sinus rhythm, i.e., normal heart beat.

• In one of the more comprehensive systematic reviews of the literature, of digitalis for treating individuals with heart failure who are in normal cardiac rhythm were analyzed.

• The results show that digitalis had 31% probability of decreased the probability of clinical deterioration by 69%, preventing deterioration in the clinical status of the patient.

• This means that digitalis had no effect on long-term death rates, significantly decreased the need for hospitalization for worsening heart failure, and significantly improved clinical cardiac symptoms.

• Digoxin is effective for treating heart failure accompanied by chronic atrial fibrillation with a rapid ventricular rate, because digoxin slows the ventricular rate and results in a positive inotropic effect.

• Digoxin decreases the rate of beating of the heart ventricles, the chambers of the heart that push blood out to the body, in most patients with atrial fibrillation.

• For many years, digitalis was the only drug available for rate control in patients with atrial fibrillation resulting in much of the clinical experience with rate control being based on the sole use of this drug.

Depression• Hypericum, an extract of the flower of St. John’s

wort (Hypericum perforatum L), has been used for the treatment of depression for centuries.

History• The use of St. John’s wort has risen dramatically in

the United States as well as worldwide. • European physicians have used hypericum to treat

mild-to-moderate depression for some time. • In the United States, St. John’s wort accounts for

about 10% of all herbal medicine sales and currently is one of the largest selling “natural” remedies.

• The three top-selling herbal products in the United States are Ginkgo biloba L., St. John’s wort, and ginseng.

• In the most recent review of clinical trials in 2007, the evidence suggests that St. John’s wort has greater efficacy than placebo and equal efficacy to low-dose tricyclic antidepressants, such as imipramineTM, in most trials for treating mild-to-moderate depression.

• Several other studies indicated that St. John’s wort was as effective as selective serotonin reuptake inhibitors (SSRIs) for treating depression.

• In summary, most of the evidence suggests that St. John’s wort was more effective than placebo, but as effective as standard antidepressants, for treating mild-to moderate depression.

• The evidence for major depression is less well defined.

Mechanism• Constituents of extracts of St. John’s wort under

investigation as the effective pharmacologic agents include hypericins, hyperforin, polycyclic phenols, and pseudohypericin.

• It has been proposed that hyperforin inhibits the synaptic reuptake of several neurotransmitters, including serotonin, dopamine, and norepinephrine.

• Hypericin has not been confirmed as the active ingredient for St. John’s wort.

• Hypericin might decrease the production of cortisol or inhibit reuptake of neurotransmitters, such as serotonin, norepinephrine, and dopamine.