Pharmaceutical Journal Vol 263 No 7066 p613
October 9, 1999 International

World congress of pharmacy and pharmaceutical sciences

Approaches to drug discovery from plants

The high standards of Spanish research in the area of bioactive natural products were emphasised at a congress symposium on September 9 at which all but one of the invited speakers were from Spanish universities. The meeting was organised by the International Pharmaceutical Federation's medicinal and aromatic plants section.

Molecules from entheogens

Plants offered by ethnopharmacology for investigation as a source of bioactive molecules included the entheogens, Professor TOMAS ADZET (University of Barcelona) said. Entheogens were substances used by communities to communicate with the non-material world. They were often regarded as sacred plants, being used not only to treat disease but also to discover the source of the disease and the means of correcting it.
The value of these substances at present was more in their potential to provide experimental models of psychosis than as treatments, since increasing evidence showed that many of them affected serotonin receptors in the central nervous system.
Entheogens described by Professor Adzet included the South American drink ayahuasca, made from a mixture of plants. He related his own experience of participating in ceremonies where it was used. In Brazil it was used under government sanction by some religious groups for the seemingly successful treatment of those with alcohol addiction. Other entheogens described by Professor Adzet were Psilocybe spp mushrooms, eaten with honey and chocolate to disguise their bitter taste, and cacti such as peyotl (Lophophora williamsii) from Mexico and related species from Peru. With these, after an initial period of nausea and vomiting, the subject experienced inner peace and hallucinations for several hours.

Value of ethnopharmacology

The value of ethnopharmacology in drug discovery was emphasised in a presentation by Professor SALVADOR CANIGUERAL (Barcelona university). He said that 75 per cent of drugs used in pharmacy that were obtained from higher plants had originally been isolated from species used in traditional medicine. Several studies had shown that the "hit rate" for active compounds was higher when plants were selected according to traditional use rather than at random.
Describing the procedure for undertaking an investigation based on ethnopharmacology, Professor Canigueral indicated that the cultures most likely to yield novel compounds were those that possessed a strong medical tradition of their own, were in areas of high biodiversity and had lived for a long time in the particular geographical area.
Giving illustrations from his own research, Professor Canigueral went on to describe a polycyanidin oligomer obtained from Croton lechlerii resin, which was used traditionally in some areas of South America to treat various diseases. It had displayed antiviral activity in vitro. Bioassay-guided studies had resulted in the isolation of the oligomer, which acted by direct binding to the viral envelope and inhibited its penetration into host cells.
Another example was a Mexican plant, Hetherotheca inuloides, which was used to treat bruises as arnica was used in Europe. Flavonoids had been isolated which inhibited both COX-1 and COX-2 enzymes.

Chemical modifications

Professor A. SAN FELICIANO (University of Salamanca) discussed the chemical modification of natural products to enhance their activity. He said that some stilbenes - such as isonotholaenic acid, isolated from an American fern, Notholaena nivea —had a variety of activities including cytotoxicity, antiadrenergic effects and weak antiprotozoal activity against Leishmania donovanii and Trypanosoma cruzi. To enhance the cytotoxic effect and provide compounds for eventual antineoplastic therapy, a series of analogues had been synthesised and tested. Particularly in phthalazinones, the activity had been improved by two orders of magnitude.
Tests with rat aorta had also shown that some of the synthetic products had reversible antagonistic adrenergic effects, making them possible candidates for bronchodilators.

Value of taxonomy

Professor DIEGO RIVERA (University of Murcia), giving a presentation on behalf of his colleagues C. Obon and F. Tomas-Barberan, discussed the value of taxonomy in discovering new drugs and aiding the production and supply of active compounds once they had been discovered.
An illustration was provided by the valuable drug paclitaxel (Taxol). The shortage of this compound, first obtained from the Pacific yew (Taxus brevifolia), had initially been a serious hindrance to its development. Investigation of related species of Taxus had revealed small amounts of paclitaxel but, more importantly, similar compounds in the leaves from which it could be produced by chemical synthesis.
Another example was rutin, a flavonoid whose derivatives were widely used to protect against venal damage and as a general antioxidant. Commercial supplies were obtained from buckwheat (Fagopyrum esculentum), which contained about 70ppm. But recent studies had shown that the common plant whose flower buds were known as capers (Capparis spinosa) contained as much as 10,000ppm rutin.

Small-scale bioassay

Professor PETER HOUGHTON (King's College London), who chaired the session and was the only non-Spanish speaker, described the advantages and disadvantages of using small-scale bioassays to detect novel bioactive molecules. This approach was extensively used in the pharmaceutical industry or by large government programmes such as the National Cancer Institute in the United States. Professor Houghton said that there were two common problems in such studies. One was the isolation of a compound that turned out to be already known, such as beta-sitosterol as an anti-inflammatory found in Oroxylum indicum. Dereplication procedures were needed to overcome this problem.

Peter Houghton: problems and successes in small-scale bioassay

The other common problem was a loss of activity following fractionation of a total extract. An example was the cytotoxic activities of fractions from Kigelia pinnata stembark. It was less easy to design tests to overcome this problem.
In spite of these drawbacks, large numbers of novel bioactive compounds had been found using this method. Examples from his own research group included antifungal terpenes from Buddleja species and antituberculosis alkaloids from Angostura bark. - Contributed.