Secondary plant metabolites and the chemical industry

The first secondary compound to be isolated in a pure form was morphine from the opium poppy, in the early nineteenth century. Although it took almost 50 years for its structure to be elucidated, this nevertheless signalled the beginning of pharmacy as an exact science of fully characterised molecules given in regulated doses. The techniques of isolation, characterisation and synthesis gradually improved during the nineteenth century, and gave rise to a modern chemical industry based not on living plants, but on the conversion of fossil plant remains, coal and oil, to the plethora of drugs, pesticides and other chemicals demanded by today's complex industrial society.

The ingenuity of synthetic chemists allowed not only the reproduction of naturally-occurring molecules, but also the production of unnatural derivatives of natural compounds, as well as completely novel unnatural substances. Wholly synthetic molecules began to make a dramatic impact on the quality of human life in the twentieth century. The pesticide DDT, for example, rid urban slums of insect pests and helped change the fortunes of combat troops during World War II. Synthetic polymers changed life everywhere. Although interest in some natural products persisted, notably those of microorganisms in the search for new antibiotics following the discovery of penicillin, living higher plants were all but abandoned as a source of inspiration or raw material for an industry confident that synthetic molecules would satisfy all needs.

By the 1950s this confidence was punctured by the realisation that unnatural pesticides were not substrates for the degradative enzymes of microorganisms which re-cycle natural waste and were accumulating in the environment causing ecological havoc (Carson, 1963). The pharmaceutical industry too faced problems. The thalidomide tragedy of the early 1960s was a stark reminder that the actions of synthetic compounds tested in rodents were not reliable indicators of their effects in humans. Unease continued during the 1970s at the lack of synthetic or microbially-derived drugs coming onto the market to combat the growing problems of cancer, diabetes and circulatory disorders. At the same time, several chemicals from higher plants were being reported as meeting contemporary needs.

The synthesis of the contraceptive steroids and the social revolution which followed in its wake was only possible in the 1960s because of the use of the steroid diosgenin from a Dioscorea species as a starting material. The serendipitous discovery, also in the 1960s, that two alkaloids from the pan-tropical weed Catharanthus rosetis, the Madagascan periwinkle, had anti-cancer properties led to the launch of vincristine and vinblastine which by 1985 had annual world sales of $100 million. Etoposide, an anti-cancer agent synthesised from a chemical in the May apple, Podophyllum peltatum, and used by native Americans for warts, had sales of $15 million by 1989, and oil of the evening primrose, Oenothera species, used by them for skin problems, had found a market for both eczema and the pre-menstrual syndrome. In the late 1980s as the problem of AIDS increased, many plant-derived chemicals were reported to have inhibitory effects against the human immune deficiency virus in vitro and to offer hope of an alternative to the few synthetic drugs available. In addition, many plant chemicals were finding their way onto the commodities market for a wide range of uses, such as food colourants and perfumes, and it was suggested that the market for these might exceed that for medicinal agents. Set against the rising climate of a public demand for 'natural' ingredients, industry has begun to take another look at higher plants (reviewed in Fellows, 1992a, b).

The re-discovery of plants comes at a time of grave concern over the rate of loss of the world's forests and other natural vegetation which might be expected to provide the new 'leads' that industry seeks. The tropical forests have shrunk since the 1940s from 15-16 million km2 to less than 8.6 million km2 and a further 1 % are destroyed and 1 % severely degraded each year (Myers, 1989). Less than 5% of the world's flora is believed to have been subject to any kind of chemical investigation. It has been suggested that profits from the industrial exploitation of plant chemicals might be diverted to pay for conservation measures which will help ensure not only a supply of raw plant material for the future but also to preserve the ecological web on which we all depend. How realistic is this proposal?

Estimates of the 'hit' rate from random screening programmes vary but are put at between 1 in 1000 and 1 in 10000, and those of the time and cost of developing a 'lead' into a marketable drug at 10 years and $200 million. Conservation of our dwindling natural resources cannot wait 10 years, so it has been proposed that companies might put money 'up front' into forest protection schemes in exchange for priority rights to develop the fruits of chemical prospecting in the area (Fellows, 1992b). The US company Merck has already invested $1 million in a pilot scheme in Costa Rica, but researcher Principe (1989) recently estimated that $3.5 billion needs to be spent now in order to preserve forests solely as a resource for the pharmaceutical industry, without taking into account the cost of forest erosion on the ecosystems.

Investment at this level is unlikely to be forthcoming unless the 'hit rate' of screening programmes improves. Screening plant extracts presents problems not experienced with synthetic or microbially-derived compounds, in particular interference by tannins (Fellows, 1992ft). Already several companies which embraced plant screening in the late 1980s are having second thoughts.

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