PINSA, 66, A, Nos. 3 & 4, May & July 2000, pp. 383 - 392.

C> Printed in India

RESURGENCE OF NATURAL PRODUCT RESEARCHA PHOENIX ACT

ABANERJI*

Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai-400 085 (India)

(Received 4 February 1999; After revision 19 May 1999; Accepted 17 June 1999)

Most of the chemical investigations on plants and other natural products are directed towards the compounds which are useful in human welfare such as drugs, agrochemicals. cosmetics etc. However. in recent years, there has been marked change in the approaches to the natural product research. Modern researchers are directed towards different frontiers which deal with the physiological and ecological significance of the secondary metabolites. Study of natural products not only provides novel bioactive compounds but also leads to the understanding of the natural processes of great importance. These. which may be called natural technology are likely to provide totally new concepts for combating diseases, pest control and improvement in agricultural production. Developments in DNA recombinant technology and genetic engineering have offered new possibilities of interspecific cloning of genes which could generate entirely new class of hybrid products of hitherto undiscovered bioactivities. However, over enthusiasm on genetic engineering should not neglect the inexhaustible genetic resources available in natural products which have largely remained unexplored. To meet the challenging resource needs of the ever increasing population. it is necessary to revitalize the investigations of natural products which would expand our resource base. A purpose oriented research on natural product would certainly yield rich dividend in terms of furnishing novel structures, new bioactivities and novel ecologically acceptable technologies. Changing strategies of natural product research will be discussed.

Key Words: Natural Products; Natural Technology; Pbytopharmaceuticals; Renewable Feedstock; BioCommunications; Biotechnology; Bioremediation; Green Technology; Genetically Engineered Metabolites; Combinatorial Strategies

Introduction

Natural product chemistry is as old as organic chemistry. The original impetus to organic chemistry came from the natural product research 1• Most of the earlier studies were directed towards medicinally important plants. But recent advancements In modem biology and developments in the instrument technology have brought about revolution in this branch of bioorganic chemistry. The immense potential of natural products due to their unlimited bio- and chemodiversity is being increasingly realised by the chemists, biotechnologists and biologists and has created new awareness'". In addition to new pharmacologically active agents, plants are also sources of renewable feedstocks for manufacturing wide range of industrial products from cosmetics to lubricant and fine chemicals 4• The research on

·Present Address: Organic and Biomolecular Unit. Regional Research Laboratory, Trivandrum-695.019 (Kerala)

natural products has also unravelled the mechanisms of many bioprocesses and have opened up new fronts in biotechnology'. In an anthropocentric approach to nature, the studies on plants and other natural products were mainly confined to their utility towards human welfare. However, the scenario is fast changing. Occurrence of an endless array of organic structures have directed the natural product research towards newer frontiers dealing with biotechnology, physiology and ecology. What are the significances of these compounds for the organisms which produce them at the considerable expense of resources? Substantial evidences have accumulated in recent times which show that the naturally occurring chemicals (secondary metabolites) play important roles in the interactions between different organisms in the Biosphere", Therefore, they are expected to have wide range of bioactivities. The present article deals with the enhanced scope of natural product research and emphasises the non-medicinal uses of the naturally

384

occurring compounds and their possible application in Biotechnology.

Genesis of Secondary Metabolites

Plants are the bioreactors of nature. During the long course of history of the earth, elegant chemical processes have evolved which furnish an array of molecular architectures utilising very simple molecules as starting materials and under extremely mild reaction conditions. Through the remarkable process of photosynthesis, the green plants (autotrophs) convert carbon dioxide

. (inorganic carbon) to the reduced form of carbon (i.e. carbohydrates), using only water and abundantly available light energy. ill the process, oxygen is set free which is indispensable for the sustenance of life in our eco-system. The energy for almost all the biological activities are directly or indirectly derived from the reduced carbon compounds thus synthesised. The scale of the photosynthetic activity is stunning. Each year, tens of billion tons of carbon are taken from the atmospheric CO2 and are converted into incredibly complex primary and secondary metabolites such as nucleic acids, carbohydrates, proteins, amino acids, heterocycles, isoprenoids, phenolics, alkaloids, lipids etc. through remarkable biochemical reactions. An understanding of the technologies which the Nature uses and may be called "Natural Technology" will offer entirely new concepts for the development of eco-friendly technologies 7•

Plants as renewable source of chemicals have been recognised by man even before the dawn of civilization. Mainly through intuition and keen sense of observation, the ancient man had discovered many useful properties of plant products. Timber has been in use for construction purposes, cellulose as fibre, colouring matters as dyes and food additives and natural fats and vegetable as industrial products and phytochemicals as drugs, cosmetics'", Even some of the animals have learnt to use certain natural products to their advantage". The oriental systems of medicine evolved out of the wisdom and experiences accumulated through generations. Some of the ancient remedies have been welldocumented in Ayurveda, Unani, Tibetan, Kampo (Japan), Jamu (Indonesia) and Chinese systems of

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traditional medicine. However, often the folkmedicines are kept closely guarded secret and are held by select communities or traditional healers. In spite of the fact that about 80% of the world population still use phytotherapy for their primary health care, this branch of sciences has not received the attention it deserves'".

Evolution of Natural Product Chemistry With the advent of organic chemistry, it was logical to relate the properties of plants with their chemical constituents. Thus, many drugs such as morphine, strychnine, brucine were isolated in the pure form in the last century. However, their structure elucidation had to wait till appropriate techniques became available!'. Development of powerful instrumental methods such as IR, UV, NMR, mass spectrometry, X-ray crystallography, ESR, neutron diffraction have contributed greatly towards bringing the natural product research in its present form. Concurrently, there has been revolution in the methods of isolation and purifications (e.g. TLC, HPLC, HPTLC, supercritical fluid extraction, electrophoresis, GPC etc.).

Now, it is possible to isolate and characterise even the minor and labile constituents, Recent awareness of biotechnical potential of natural products has provided additional impetus to research in this branch of Bioorganic Chemistry. Conventional research on natural products was mainly confined to the study of the constituents which were readily isolable, The stance has changed with time. The modem natural product research is mission-oriented and is guided by biological activity. The chemical and biological studies are carried out concurrently. The bioassaydirected fractionations of the extracts have resulted in the isolation of compounds with hitherto unknown bioactivities, even when present as minor constituents. Understanding of the fundamental aspects of diseases and availability of the relevant enzymes, receptors, cell systems etc. have led to the development of high throughput assays which permit screening of large number of test samples in a short span of time'", This has contributed greatly towards the drug discovery programmes since using combinatorial approach, many structurally related compounds can be prepared expeditiously.

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However, use of extracts of natural products has the additional advantage over synthetic combinatorial approach since not only large numbers but also wide variety of classes of compounds are screened at a time. This greatly enhances the chances of the discovery of the active principles or the lead compounds.

It is often not realised that even in present times, the plant derived products contribute greatly towards wide range of industries such as pharmaceuticals, fine chemicals, agrochemicals, cosmetics, industrial chemicals etc. The natural products also provide advanced raw materials for the high-value drugs such as steroids. Of the world's 25 best selling pharmaceuticals agents, about half are derived directly or indirectly from natural sourcesv':". Cardiac glycosides from Digitalis purpurea, tranquilizer reserpine from Rauvolji.a serpentina, analgesics morphine and codeine from Papaver somniferum are some of the examples of drugs which were discovered several decades ago but are still in use. The retail value of plant-based pharmaceuticals in US alone is estimated to be $ 15 bn 15. In addition, the natural product research has stimulated the organic chemists to synthesise active principles and their analogs with a view to provide compounds with improved bioactivities. Taking cues from nature, organic chemists have been able to mimic the synthesis of several compounds following biosynthetic approach'f. Biomimetic synthesis have great relevance towards the development of Green Chemistry'".

New Phytopharmaceuticals From Natural

Products

Revi val of interest in the natural products has resulted in the isolation and characterisation of several new phytopharmaceuticals''. Isolation of complex diterpenoid alkaloids taxol (placlitaxel) from the pacific yew, Taxus brevifolia has attracted much attention in recent times due to its remarkable action against breast and ovarian cancer by a unique mode of mechanism. It acts by promoting microtubule assembly and stablizing microtubules by polymerisation 17. Camptothecin, initially isolated from the plant, Camptotheca acuminata, has been converted into analogs having more desirable anti tumour activity and holds great

promise for the future treatment of cancer". The camptothecin analogs act by yet another novel mechanism by inhibiting the topoisomerase enzymes. The topoisomerases alter the linking relationships within or between DNA molecules'". Ethnobotanical considerations have played important role towards the discovery of several remarkable drugs. For centuries, Artemisia annua has been used in China for the treatment of malaria and other fevers. The active principle, artemisinin, a novel sesquiterpene lactone peroxide, has many advantages over the conventional anti-malarial drugs " and has been found to be effective against cerebral malaria as well as several resistant varieties of parasites. Interesting results were obtained from the investigations on some of the drugs prescribed by tribal medicine men. African tribes have been using berries from the plant, Maesa lanceolata for protection against cholera. It has now been established that the active principle, measamim act by the disruption of an important enzyme KDO transferase which is essential for cell wall biosynthesis": Kani tribes of Agasthyar hills of Kerala have been using Arogyappacha tTrichopus zeylinicus) as health food. Its properties are similar to those of ginseng".

Though many of the drug discoveries were initiated from the studies on plants which were reported to have medicinal properties, it may not be wise to neglect the vast majority of other plants. Serendipity has played important part in the discovery of many drugs23.24• The antileukemic acitivity of vincristine and vinblastine, isolated from Catharanthus rose us were discovered by chance while searching for hypoglycaemic agents'", Recently, bioassay directed screening of extracts of plants collected at random, resulted in the isolation of the steroid glycosides, OSW-1 from the ornamental plant, Ornithogalum, saundersiae (Liliacae). It was found to be less toxic but more potent against human lung cancer and leukemic cells when compared to taxol and other drugs currently used". Bioassay directed screening of the extracts of the bark of Ziziphus maurtttana was found to show selective cytotoxicity on cultured human melanoma cells". Bioassay directed fractionation of the extract led to the isolation and characterisation of betulinic acid which is a melanoma-specific cytotoxic agent. It is important to note that the antitumour activity of

3~6

betulinic acid is mediated by the induction of apoptosis and provides new target for cancer therapy". These discoveries open up a new front towards discovery of anticancer drugs.

Cytotoxic principles, epothilone A and related metabolites isolated from the myxobacteria of the genus Sorangium show remarkable biological properties including antitumour activities. Their mode of action is similar to those of taxol ". It is interesting to note that three-dimensional structures of epothilones show considerable similarities with that of taxo!. They have common binding site on the microtubes. Unlike taxol, epothilones have the advantage that these can be produced in large quantines by fermentation. Realising the importance of the compounds, several syntheses of these compounds have been completed within a short span.

Phenolic oxygen heterocycles constitute one of the most diversified and widely distributed class of natural products and have been subjected to extensive chemical investigationsf". Vegetables and fruits which are important components of human diets are rich sources of flavonoids, phenolics, carotenoids etc. Till recently, only scant attention was gi ven to the study of their biological activities although very significant amounts of these are ingested by humans through the dietary uptakes. Therefore, investigations on their role have been initiated and many remarkable bioactivities have come to light.

The antioxidant activity of flavonoids was described several decades ago ", Recently, it has been realised that oxidative damages are responsible for a variety of degenerative diseases such as Alzheimer disease, diabetes, cardiovascular diseases, arthritis'3. Therefore, there has been renewed interest in f1avonoids and related cornpounds T'". Flavonoids are also known to inhibit numerous diverse enzymes. For example as a result of systematic screening of f1avonoids, cirsiliol, 3/A1,5-trihydroxy-6, 7 -dimethoxyflavone and related compounds were found to be potent selective inhibitor of 5_lipoxygenase37.38. Isoprenylated flavonoids from Morus sp. exhibit

inhibitory activrty against testosterone-Sureductase which has been implicated in certain androgen dependent conditions". Many dietary f1avonoids exert protective action by modulating carcinogenesis and mutagenesis. Some of them

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show significant antitumour activiues, antihepatotoxicity, immunomodulatory, anti-inflammatory and insect antifeedant activity amongst other important properties of f1avonoids.

Compared to animals, plants do not have welldefined immune systems. Therefore, on ecological considerations, it can be' anticipated that the plants would synthesise antiviral compounds for their own protection from viral attack'". Indeed, plants are good sources for bio-immunornodulators such as adaptogens and nootropic compounds. Adoptogens raise the non-specific resistance by altering the endocrine functions of the adrenal gland axis and raising ACTH and corticoid levels'". These plants are useful for the treatment of stress induced conditions. Ginseng iPanax ginseng), Ashwagandha (Withania somniferai, Gingko biloba, Siberian ginseng (Eleutherococcus senticocus), Rhodiola rosea, Sedum rosea (occur in Laddakh and Siberia) and tulsi (Ocimum sanctanumi are some of the examples which are known for their anti-stress activities. Amrita tTinospora cordifolia) which is extensively used in several Ayurvedic formulations show remarkable imrnunornodulatory activity?'. A bioassay directed fractionation has led to the isolation of the active principle'", The discovery of inhibitory activity of some of the complex oxygen heterocycles against reverse transcriptase opens up new possibilities for the development of non-nucleosidic antiviral agents. In this connection reference must be made of calanolides, the complex coumarins isolated from Calophyllum species which exhibit anti-HIV activity". The dimeric naphthylisoquinoline alkaloids isolated from Ancristocladus korupensis hold considerable promise as anti-AIDS agents". Polysaccharides which frequently occur in plants, marine natural products and algae, show significant anti-HIV and other therapeutic acti vities 45.

Natural Product Research In New Perspective During the course of evolution, plants have acquired effective defence mechanisms which secure their survival amidst hostile environments' and enemies. Amongst the interactions, those between plants and insects are better understood'f". Thick 'cuticular waxes, thorns, prickles, sticky hairs are some of the familiar

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NATURAL PRODUCT RESEARCH -A NEW PERSPECTIVE

• Biocommuulcation

Bioass7Y Directed * Apoptosls

"'-Known A • Anti-metabolites

~ct~'

,-______ New Technology

Natural Products ___. • N2 Fixation

* IPM for Insect Control * Photosynthesis

* Green Technology (Biocatalyst)

Pharmaceuticals

(Vincristine, Reserpine, Taxol, Epothilone)

1 Synthesis Raw Materials (For Industries)

/s)1rthesis Industrial Products

/j

New Activities • Genl! Inducer

New Molecules"'_ Biosynthesis ---+ Biotechnology

I

\ I

New Leads

Organic Synthesis *Synthetic Challenge

= Combinatorial Synthesis

CHART I

protective features. Though less obvious, more important and subtle defense mechanisms are based on chemicals which protect the plants from the attacks of insects, microbes and other predators. An understanding of these, which may be called "natural defense technologies" might therefore provide cues for the development of new biotechnical procedures for pest control measures based on ecologically acceptable biocides. Thus, the investigations on the role of secondary metabolites in the ecodynamics of plants and insects are important areas in the newly emerging discipline of Bioorganic Chemistry called "chemical ecology .. 7.

The divergent classes of chemicals which the plants and other organisms produce offer ecological advantage by making them unsuitable for utilisation by insects and other predators by imparting repellency, toxicity, unpalatability or biochemical incompatibility. Production of toxins is one of the most successful defence strategies which organisms have developed": Some of them

• Renewable Souce s - High- Value Chemicals

• B io-R e mediation

* Genetically Engineered Products

have application as drugs or pharmacological agents while others provides models for synthesis for improvement of bioactivity. The synthesis of whole range of synthetic pyrethroids was based on the lead obtained from the naturally occurring insecticides, pyrethrins, isolated from the flower

h d f CI I .:;: r· 48

nea S 0 irysant 1emum cmeranjOtlllm.

Compared to the terrestrial plants, manne organisms produce experience harsh ecological environment and show more pronounced chemodiversity. Tetrodotoxin, a toxin isolated from the Japanese culinary puffer fish Fugu rubripes rubripes is valuable because it inhibits the sodium permeability of nerve membrane resulting in the paralysis of peripheral nerves and is an important compound for biochemical investigations.

A major sophisticated type of defence is provided by the micromolecular constituents of the organisms which may .not cause instantaneous mortality but their effects are manifested by biochemical intervention of important

388

physiological functions of the predators. Thus, highly potent insect growth regulators which occur in many plants can disturb the precise synchronisation of development of insect-predators by causing hormonal imbalance resulting in suppression of reproduction or bringing about behavioural changes. Such chemical agents can have important role in the development of

. d 49 A

integrate pest management programmes. s an

offshoot from the results obtained from basic research, growth regulators are finding use in agrobased industry such as sericulture, apiculture or aquaculture. Phytoecdysoids and other growth regulators are being used to improve the yield and quality of silk50.

Based on ecological consideration, it is anticipated that the secondary metabolites would exhibit diverse types of bioactivities. Even some of the simpler molecules may have profound ecological and physiological significance. Nature has developed incredible communication systems (biocommunication) which are mediated through chemical signals51.52. For example, host recognition is vital for the parasitic organisms which are dependent on specific hosts. Here again, chemical factors are involved. Luteolin, a simple flavone, was characterised as the gene-inducing substance for establishing the symbiotic relation between the bacteria, Rhizobium sp with their hosts 53 • These compounds act as molecular switches and control molecular events of" great importance for the biological nitrogen fixation. A remarkable example of biocommunication has been observed recently with the tobacco plants. The viral-infected tobacco plants alert its neighbourhood healthy plants by emission of vapour of methyl salicylate. In the healthy plant methyl salicylate is converted into' the salicylic acid which activates the molecular marker gene PRI-I for acquired viral resistance and provides protection against the impending viral infection. This is the first example of biocommunication between infected and healthy plants",

The biocommunications in insects are mediated by the chemical substances, pheromones which are produced in exceedingly small amounts. Pheromones control numerous facets of behaviour of other members of the same species. Biocommunicatory substances offer eco-friendly alternatives for controlling the insect pests of

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economic importance. Being chemically simple, most of these compounds are amenable to synthesis and are finding increasing application in the integrated pest management programme for monitoring, mass trapping, or mating

d· . 5556 isruption ..

Plants which are fixed through root system to the substrate, often face situation where the levels of toxic metals in the soil are abnormally high. As an evolutionary requirment some plants have developed the capacity to hyperaccumulate toxic metals. Metal detoxification by the plant could be due to passive adsorption, or fixation by chelation. Phytochealatins which are small peptides, have been found to protect the plants from the heavy metal poisoning by chelating them to less toxic complexes and transporting them to safer sites such as cell-vacuoles. In fact, induction of synthesis of phytochelatins has been observed in many plants when challenged with toxic metals". Bioremediation is likely to emerge as eco-friendly and cost-effective procedure to clean up of contaminated sites, industrial effluents and radioactive waste58.59.

In modem approach to natural product research, emphasis is given to bioactivities and the isolation is directed by bioassay. This has led to the discovery of hitherto unknown bioactivities from both known as well as new agents. For example, though garlic is known for many medicinal and curative properties, additional new bioactivities were discovered recently. Thus the garlic constituents, diallyl disulfide which was identified as the insecticidal agent'" has now been found to be a chemo-preventive agent for skin-cancer" and an inhibitor of HMG-CoA reductase'? while another component ajoene, shows remarkable antithrombotic and anti-platelet aggregation activities63.64. Recently, the antioxidant property of allicin, active principle of garlic has been reported". Discoveries of betulinic acid (from Ziziphus mauritiana)27 and OSW-I (from ornmental plant, Omithogalum saundersiae) as anticancer agents were possible since the isolations were directed by bioassays".

Biotechnology in the Synthesis of Complex Biomolecules

Often, natural products may not be the practical

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389

source for bioactive compounds due to low occurrence or limited availability of the source. The spectacular progress in chemical sciences has made most of the natural products amenable to synthesis. Although synthesis of a large number of natural products have been achieved, only a few of them are of commercial interest. Natural products remain the source of such compounds. There are other cases, where the compounds are not amenable to any practical synthesis due to their complex molecular architecture. The advent of rec?~binant DNA technology has opened up unhnuted possibilities. Commercial preparation of human insulin is one of the earliest examples of application of recombinant DNA technology. Traditionally, insulin has been derived from porcine products. In 1977, human insulin was expressed in a bacterium and its commercial manufacture became a reality in 1983. Production of human growth hormone and interferons are the other examples which reflect the power of this new technology.

Plants as resource of bioactive compounds have some limitations. Many of the plants of commercial importance may belong to endangered list. Availability of plants may be scarce or may not be available at all due to geographical reasons. Therefore, in order to expand the resource base attempts are made for alternate resources. For example, the anti tumour agent, camptothecin was isolated from Camptotheca acuminata. Later, Mappia foetida, (Nothapodytes foetida) a tree which grows abundantly in the Western ghats of India, was found to be an excellent alternate source of the drug'". Sometimes, the plants may provide compounds which may not be active itself but can be transformed into high value pharmaceuticals by synthetic manipulations. This is exemplified by the occurrence of diosgenin in Dioscorea sp. which forms the starting material for the whole range of steroid drugs. More recently, issues related to limited supply of taxol have stimulated search for alternate sources. Though taxol was not obtained' in substantial amounts, several taxane derivatives were isolated from the foliage of Taxus sp. Methods and technology for the conversion of precursors for taxa I such as baccatin ill or 10- deacetylbaccatin have been successfully developed 17.

Emerging Trends in Natural Product Research Production of secondary metabolites by tissue culture, often called plant biotechnology is another emerging area'". It is possible to tap the unlimited biochemical wealth of plants by inducing cell cultures to produce specific valuable chemicals. This technology is particularly useful when the plants sought for their chemicals are not readily available due to geographical or climatic factors. ~easibility of this technology rests on its ability to induce and select genetically stable whole plant or cell cultures that over-produce specific chemicals. Tissue culture is more readily amenable to genetic and biochemical manipulation and it is possible to alter the biosynthetic pathways in the regenerated plants in the desired direction. Several somoclonal variants with modified levels of secondary plant metabolites have been observed. Another potentiality of this area of biotechnology is the ability of plant cell, microbes or isolated enzymes to biotransform inexpensive precursors to high value products'".

For the development of drugs or other bioactive compounds, optimisation of bioactivities often require modifications of lead structures. Conventionally, this is achieved by chemical means, either by total synthesis or wherever possible by chemical transformations. However, some of the natural products may not be amenable to modification by chemical means due to complexity of their structures. Recently, this has been achieved by diverting the normal biosynthetic machinery into producing analogs. Taking advantage of the less stringency of the enzyme action, excess of false precursors are used to dilute the endogenous pool of precursors to direct the biosynthesis to desirable end-products. Commercial production of analogs of pencillin with improved bioactivities is an example of application of this approach.

The yield of taxol from T. brevifolia is very low.

In spite of extensive search, viable alternate source of taxol has not been found so far. Though elegant total syntheses of taxol have been achieved commercial method for large scale preparation is not available17• Therefore, procuring sufficient amounts of taxol remains a vexing problem. Fungal sources for taxol have also been explored. The yew tree fungus, Taxomyces andrea/we and

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Pestalotiopsis microspora have been found to contain taxol, though in small quantities. The gene complex for the biosynthesis of taxol in T. andreanea has been isolated'". Cell culture have raised hopes as these systems are amenable for manipulation. Best yield of taxol produced by cell culture have not been economical so far. However a breakthrough has been achieved wherein use of cell-signal transducer, methyl jasmonate has increased its yield by several folds70. These developments are likely to contribute towards the commercial production of taxol by biotechnical procedure.

In an unconventional approach, a remarkable synthesis of vitamin B12 has been achieved starting with 5-aminolaevulinic acid and using a battery of enzymes. The complete elucidation of biosynthesis allowed the identification of the relevant genes which were cloned and over expressed. The total synthesis was achieved in a single test tube by recombining all the twelve enzymes 71.

A more elegant approach to synthesis of compounds is to engineer the biosynthetic pathways by incorporating genes recruited from other related organisms. The feasibility of interspecific cloning was demonstrated by Hopwood and co-workers for the first time in 198572• Subsequently many genetically engineered syntheses have been carried out successfully73-75. Genetically engineered E. coli has been used frequently for the preparation of high value chemicals. Now the biomachinery of plants has also been put to use for genetic- engineering". Since native plants can be cultivated as agricultural crops, emphasis has been to introduce the desirable genes in such plants. This approach simplifies the down-stream processing which is often the major hurdle in the development of biotechnical processes.

Plants as bioreactors, offer unlimited potential for the preparation of chemicals of industrial importance. Oleochemicals such as vegetable oil, fish oil and animal oil have been in use since ancient times. These are still used in many parts of the world though in much smaller scale compared to petroleum products. Oleochemicals can be converted by comparatively simple operations into value added products such as polymer feedstocks", For example, rapeseed oil contains unsaturated fatty acids which can be degraded into industrially

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important feedstocks like brassylic (Cl3), azelaic (C9) and adipic (C6) acids. In a futuristic approach, a gene from Caifornia Bay tree which is involved in the lauric acid synthesis was transferred. to a variety of rapeseed plant. The transgenic rapeseed produced substantial quantities of lauric (Cd acid which is a feedstock chemical for the manufacture of detergents. Bipol, poly hydroxy butyrate (PHB), is a biodegradable polymer which is finding increasing application in industry, particularly food industry. It is produced by the bacterium Alcaligene eutrops. The relevant genes from the bacterium was transferred to rapeseed plants which started producing biopol.

The global impact of oil crisis of 1973-74, necessitated the development of alternate sources of energy. A systematic search for biofuels from plants led Calvin to discover many hydrocarbon producing plants which can be used as fuel". Production of variety of wealth creating products from plant and microbial resources such as biopolymers, biodisels, fatty acids, industrial raw materials, designer starch, food additives, pharmaceuticals etc." has been successfully demonstrated using green technology".

In recent years, attempts have been made to develop efficient strategies to generate molecule with pre-defined properties. Taking cues from the combinatorial strategies of nature, it is feasible to generate novel molecules with entirely new functions using principles of organic synthesis, biology and physics. With this, the molecular synthesis has entered into a new era. This approach has been successfully demonstrated for the synthesis of some active compounds".

Conclusions

Natural products have been in use for human welfare from time immemorial. Recent developments in biology and advances in instrument technology have brought about a revolution in modem natural product research. In addition to be a source for medicinal products, it has contributed greatly towards the understanding of natural processes and providing new concepts and technologies. Developments in organic synthesis, biotechnology, molecular biology and genetic engineering have opened up new possibilities of interspecific cloning of genes

RESURGENCE OF NATURAL PRODUcr RESEARCH

A Banerji Bioelectrochemistry and Bioenergetics 27 (1992) 105

6 E A Bell and B V CharI wood Secondary Plant Products Springer-Verlag New York (1980)

7 A Banerji Insect Chemical Ecology (Ed I Hrdy) Academia Prague (1991) 235

8 L Fellows LAncet 339 (1992) 1330

9 E Rodriguez, M Aregullin, S Noshida, R Wrangham, Z Abramowski, A Finlayson and G H N Towers Experientia 41 (1985) 419

ION R Farnsworth Bioactive Compounds from Plants (Eds

D J Chadwith and J Marsh) Wiley Chinchester (199m 2 34 R A Larson Phytochemistry 27 (1988) 969

J D Phillipson Phytochem 38 (1995) 1319 35 R Kahl Protective and adverse biological actions of

12 J R Broach and J Thorner Nature 384 (1996) phenolics antioxidants in Oxidative Stress, Oxidants and

(Supplement 7 Nov) 14 Antioxidants (Ed H Sies) Academic Press New York

M J O'Neill and 1 A Lewis Human Medicinal Agents (1994) 225

from Plants (Eds A Kinghorn and M F Balandrin) 36 Potterat Curr Org Chem 1 (1997) 415

American Chemical Society Washington (1993) 48 37 T Horie, M Tsukayarna, H Kourai, C Yokoyama, M

Furukawa, T Yoshimoto, Yamamoto, S Watanbe-Kohno 14 D G Kingston The Practice of Medicinal Chemistry (Ed

C G Wermuth) Academic Press New York (1996) 101 and K Ohata J Med Chem 29 (1986) 2256

38 Y Kimura, H Okuda, T Normuda, T Fukui and S Archi J

15 A Florence Chem lndust (1995) 572 Nat Prod 49 (1986) 639

16 P T Anastas and T C Williamson (Eds) Green Chemistry: 39 T Nomura and T Fukai Planta Medica 42 (1981) 79

Frontiers in Benign Chemical Synthesis and Processes 40 H Wagner J Ethnopharm 38 (1993) 105

Oxford Univ Press (1998) 41 U M Thatte and S A Dahanukar Phytotherapy Res 3

K C Nicolaou, W M Dai and R K Guy Angell! Chem lnt (1989) 43

Engl33 (1994) 5 42 G J Chintalwar, A Goel, A T Sipahimalani, A Banerji, P

18 M E Wall and M C Wani Human Medicinal Agents from F Sumariwala R Ramakrishnan and K B Sainis

Plants (Eds A D Kinghorn and M F Balandrin) American Phytochemistry (accepted)

Chemical Society Washington (1993) 149 43 T C McKee, W R Fuller, C D Covington, J H Cardellina,

19 K Drilica and R J Franco Biochemistry 27 (1988) 2253 R J Gulakowski, B L Krepps, J B McMahon and M R

20 A R Butter and Yu-Lin- Wu Chem Soc Rev (1992) 85 Boyd J Nat Prod 59 (1996) 754

21 Anonymous Natural Drugs Chem Br (1984) 598 44 K P Manfredi, J H Blunt, J B Cardellina, L L Mcmohan,

22 P Pushpangadhan, S Rajasekharan, P K Rathesh Kumar G M Pannell and M R Boyd Med Chern 34 (1991) 3402

C R Jawahar, V Velayudhan Nair, N Lakshmi and L 45 j C McAuliffe and 0 Hindgaul Chern Indust (1997) 170

Sarada AmmaAncient Sci VIII (1998) 13 46 R Stevenson Chem Br 34 (1998)

23 S K Miller New Scientists (1993) 12 47 M Lusznaik and J Pickett Chem Br 34 (1998 July) 29

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(1958) 882 49 A Banerji Biotechnological Perspectives ill Chemical

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which could generate entirely new class of hybrid products of hitherto undiscovered bioactivities, It is almost certain that these disciplines will come closer in future and with increasing control over the genetic machinery, it will be possible to execute programmed synthesis of desired molecules78,79, However, over enthusiasm for gene splicing should not ignore the inexhaustible genetic resource of the natural products which are

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