Natural: What is Natural?
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Natural product

A natural product is a chemical compound or substance produced by a living
organism - found in nature that usually has a pharmacological or biological activity
for use in pharmaceutical drug discovery and drug design. A natural product can
be considered as such even if it can be prepared by total synthesis.

Not all natural products can be fully synthesized (combine various components into

new whole) and many natural products have very complex structures that are too

difficult and expensive to synthesize on an industrial scale. These include drugs such

as penicillin, morphine, and paclitaxel (Taxol). Such compounds can only be harvested

from their natural source - a process which can be tedious, time consuming, and expensive, as well as being wasteful on the natural resource. For example, one yew

tree would have to be cut down to extract enough paclitaxel from its bark for a

single dose.^[1] Furthermore, the number of structural analogues that can be

obtained from harvesting is severely limited.

A further problem is that isolates often work differently than the original natural

products which have synergies and may combine, say, antimicrobial compounds

with compounds that stimulate various pathways of the immune system:

Many higher plants contain novel metabolites with antimicrobial and antiviral properties. However, in the developed world almost all clinically used chemotherapeutics have been produced by in vitro chemical synthesis. Exceptions, like taxol and vincristine, were structurally complex metabolites that were difficult to synthesize in vitro. Many non-natural, synthetic drugs cause severe side effects that were not acceptable except as treatments of last resort for terminal diseases such as cancer. The metabolites discovered in medicinal plants may avoid the side effect of synthetic drugs, because they must accumulate within living cells.^[2]

Semisynthetic procedures can sometimes get around these problems. This often

involves harvesting a biosynthetic intermediate from the natural source, rather than

the final (lead) compound itself. The intermediate could then be converted to the final product by conventional synthesis. This approach can have two advantages. First, the intermediate may be more easily extracted in higher yield than the final product itself. Second, it may allow the possibility of synthesizing analogues of the final product. The semisynthetic penicillins are an illustration of this approach. Another recent example is

that of paclitaxel. It is manufactured by extracting 10-deacetylbaccatin III from the needles of the yew tree, then carrying out a four-stage synthesis.

 

Despite the potential limitations of natural products detailed above, these small

molecules provide the source or inspiration for the majority of FDA-approved agents

and continue to be one of the major sources of inspiration for drug discovery. In

particular, these compounds are important in the treatment of life-threatening

conditions.

 

Natural sources

Natural products may be extracted from tissues of terrestrial plants, marine organisms

or microorganism fermentation broths. A crude (untreated) extract from any one of

these sources typically contains novel, structurally diverse chemical compounds, which

the natural environment is a rich source of.

Chemical diversity in nature is based on biological and geographical diversity, so researchers travel around the world obtaining samples to analyze and evaluate in

drug discovery screens or bioassays. This effort to search for natural products is

known as bioprospecting.

 

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The plant kingdom

Plants have always been a rich source of lead compounds (e.g. morphine, cocaine, digitalis, quinine, tubocurarine, nicotine, and muscarine). Many of these lead

compounds are useful drugs in themselves (e.g. morphine and quinine), and others

have been the basis for synthetic drugs (e.g. local anaesthetics developed from

cocaine). Clinically useful drugs which have been recently isolated from plants include

the anticancer agent paclitaxel (Taxol) from the yew tree, and the antimalarial agent artemisinin from Artemisia annua.

 

 

Plants provide a large bank of rich, complex and highly varied structures which are

unlikely to be synthesized in laboratories. Furthermore, evolution has already carried

out a screening process itself whereby plants are more likely to survive if they

contain potent compounds which deter animals or insects from eating them. Even

today, the number of plants that have been extensively studied is relatively very

few and the vast majority have not been studied at all.

The microbial world

Microorganisms such as bacteria and fungi have been invaluable for discovering drugs

and lead compounds. These microorganisms produce a large variety of antimicrobial

agents which have evolved to give their hosts an advantage over their competitors in

the microbiological world.

The screening of microorganisms became highly popular after the discovery of penicillin. Soil and water samples were collected from all over the world in order to study new bacterial or fungal strains, leading to an impressive arsenal of antibacterial agents such

as the cephalosporins, tetracyclines, aminoglycosides, rifamycins, and chloramphenicol.

 

Although most of the drugs derived from microorganisms are used in antibacterial

therapy, some microbial metabolites have provided lead compounds in other fields of medicine. For example, asperlicin - isolated from Aspergillus alliaceus - is a novel antagonist of a peptide hormone called cholecystokinin (CCK) which is involved in

the control of appetite. CCK also acts as a neurotransmitter in the brain and is

thought to be involved in panic attacks. Analogues of asperlicin may therefore have potential in treating anxiety. Other examples include the fungal metabolite lovastatin, which was the lead compound for a series of drugs that lower cholesterol levels, and another fungal metabolite called ciclosporin which is used to suppress the immune

response after transplantation operations.

 

The marine world

In recent years, there has been a great interest in finding lead compounds from marine sources. Coral, sponges, fish, and marine microorganisms have a wealth of biologically potent chemicals with interesting inflammatory, antiviral, and anticancer activity. For example, curacin A is obtained from a marine cyanobacterium and shows potent

antitumor activity. Other antitumor agents derived from marine sources include eleutherobin, discodermolide, bryostatins, dolostatins, and cephalostatins.

 

Animal sources

Animals can sometimes be a source of new lead compounds. For example, a series of antibiotic peptides were extracted from the skin of the African clawed frog and a

potent analgesic compound called epibatidine was obtained from the skin extracts of

the Ecuadorian poison frog.

 

Venoms and toxins

Venoms and toxins from animals, plants, snakes, spiders, scorpions, insects, and microorganisms are extremely potent because they often have very specific interactions with a macromolecular target in the body. As a result, they have proved important tools

in studying receptors, ion channels, and enzymes. Many of these toxins are polypeptides (e.g. ɑ-bungarotoxin from cobras). However, non-peptide toxins such as tetrodotoxin

from the puffer fish are also extremely potent.

 

Venoms and toxins have been used as lead compounds in the development of novel

drugs. For example, teprotide, a peptide isolated from the venom of the Brazilian viper,

was the lead compound for the development of the antihypertensive agents cilazapril

and captopril.

 

The neurotoxins from Clostridium botulinum are responsible for serious food poisoning (botulism), but they have a clinical use as well. They can be injected into specific

muscles (such as those controlling the eyelid) to prevent muscle spasm. These toxins prevent cholinergic transmission and could well prove a lead for the development of

novel anticholinergic drugs.

 

Traditional Medicine

In the past, traditional peoples or ancient civilizations depended greatly on local flora
and fauna for their survival. They would experiment with various berries, leaves, roots, animal parts or minerals to find out what effects they had. As a result, many crude
drugs were observed by the local healer or shaman to have some medical use. Although some preparations may have been dangerous, or worked by a ceremonial or placebo
effect, traditional healing systems usually had a substantial active pharmacopoeia, and
in fact most western medicines up until the 1920s were developed this way. Some systems, like traditional Chinese medicine or Ayurveda were fully as sophisticated and
as documented systems as western medicine, although they might use different
paradigms. Many of these aqueous, ethanolic, distilled, condensed or dried extracts do indeed have a real and beneficial effect, and a study of ethnobotany can give clues as
to which plants might be worth studying in more detail. Rhubarb root has been used as
a purgative for many centuries. In China, it was called "The General" because of its "galloping charge" and was only used for one or two doses unless processed to reduce
its purgative qualities. (Bulk laxatives would follow or be used on weaker patients
according to the complex laxative protocols of the medical system.^[4]) The most
significant chemicals in rhubarb root are anthraquinones, which were used as the lead compounds in the design of the laxative dantron.

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