Natural product

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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 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, four mature yew trees have to be cut down to obtain enough paclitaxel to treat one patient. Furthermore, the number of structural analogues that can be obtained from harvesting is severely limited.

Semisynthetic procedures can sometimes get round 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.

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[edit] 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.

[edit] Screening of natural products

Usually, the natural product compound has some form of biological activity and that compound is known as the active principle - such a structure can act as a lead compound. Many of today's medicines are obtained directly from a natural source.

On the other hand, some medicines are developed from a lead compound originally obtained from a natural source. This means the lead compound:

  • can be produced by total synthesis, or
  • can be a starting point (precursor) for a semisynthetic compound, or
  • can act as a template for a structurally different total synthetic compound.

This is because most biologically active natural product compounds are secondary metabolites with very complex structures. This has an advantage in that they are extremely novel compounds but this complexity also makes many lead compounds' synthesis difficult and the compound usually has to be extracted from its natural source - a slow, expensive and inefficient process. As a result, there is usually an advantage in designing simpler analogues.

[edit] 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 a Chinese plant.

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.

[edit] 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. CKK 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.

[edit] 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.

[edit] 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 potent analgesic compound called epibatidine was obtained from the skin extracts of the Ecuadorian poison frog.

[edit] 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.

[edit] Medical folklore

In the past, ancient civilizations depended greatly on local flora and fauna for their survival. They would experiment with various berries, leaves, and roots to find out what effects they had. As a result, many brews were claimed by the local healer or shaman to have some medical use. More often than not, these concoctions were useless or highly dangerous, and if they worked at all, it was mostly because the patient willed them to work - a placebo effect. However, some of these extracts may indeed have a real and beneficial effect, and a study of medical folklore 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". The most significant chemicals in rhubarb root are anthraquinones, which were used as the lead compounds in the design of the laxative dantron.

The ancient records of Chinese medicine also provided the clue to the novel antimalarial drug artemisinin. The therapeutic properties of the opium poppy (active principle morphine) were known in Ancient Egypt, were those of the Solanaceae plants in ancient Greece (active principles atropine and hyoscine). The snakeroot plant was well regarded in India (active principle reserpine), and herbalists in medieval England used extracts from the willow tree(salicin) and foxglove (active principle digitalis - a mixture of compounds such as digitoxin, digitonin, digitalin). The Aztec and Mayan cultures of South America used extracts from a vareity of bushes and trees including the ipecacuanha root (active principle emetine), coca bush (active principle cocaine), and cinchona bark (active principle quinine).

[edit] Isolation and purification

If the lead compound (or active principle) is present in a mixture of other compounds from a natural source, it has to be isolated and purified. The ease with which the active principle can be isolated and purified depends very much on the structure, stability, and quantity of the compound. For example, Alexander Fleming recognized the antibiotic qualities of penicillin and its remarkable non-toxic nature to humans, but he disregarded it as a clinically useful drug because he was unable to purify it. He could isolate it in aqueous solution, but whenever he tried to remove the water, the drug was destroyed. It was not until the development of new experimental procedures such as freeze drying and chromatography that the successful isolation and purification of penicillin and other natural products became feasible.

[edit] See also

[edit] External links

[edit] Further reading

  • James Ralph Hanson, Natural Products: The Secondary Metabolites (2003), Royal Society of Chemistry, ISBN 0854044906
  • Xiao-Tian Liang, Wei-Shuo Fang (editors), Medicinal Chemistry of Bioactive Natural Products (2006), Wiley-Interscience, ISBN 0471739332
  • Peter B. Kaufman, Natural products from plants (1999), CRC Press, ISBN 084933134X
  • Meenakshi. Sivakumar, S. Meenakshi, Sujata V. Bhat, Bhimsen A. Nagasampagi, Chemistry of Natural Products (2005), Springer, ISBN 3540406697
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