37 



Plant Derived Bioactive Chemicals 



Therefore, the modem rational approach to drug discovery uses our knowledge of 

 disease states and biology to identify protein based targets which, when agonized 

 or antagonized, are hypothesized to yield a useful medicinal effect. However, as 

 the structure of such bioactive chemicals cannot be adequately predicted, large 

 numbers of chemicals, either analogs of enzyme substrates or hormones (102-103) 

 and/or randomly selected synthetic chemicals and extracts of natural products 

 (103-106) are screened to yield the first generation of bioactive chemicals. These 

 may yield products themselves, or the discovered structure/activity relationship 

 becomes the basis for a synthetic chemical analogue program to reduce toxicity, 

 improve biological activity and bioavailability. 



Planfg as Sources of New Medicines 



Given the historical importance of plants as sources of medicines and these 

 improved technologies, there has been a resurgence in interest in screening 

 plants for pharmaceuticals. Plants are collected on the basis of random, 

 taxonomic, and ethnobotanical information. Random collecting is based on 

 evidence that genera within families often exhibited considerable chemical 

 diversity, but species within a genus were likely to be chemically similar. Thus 

 collecting in regions of high taxonomic diversity is likely to increase significantly 

 the chemical diversity to be screened. Taxonomic collecting is based on the 

 general tendency for related taxa to contain related compounds. This leads to two 

 general applications of this method. First, when the source of a bioactive 

 compound is known, screening related taxa may jrield compovmds of similar 

 structiire with greater efficacy or reduced toxicity. A second application of 

 taxonomic collecting is to search for better sources of known compounds. 

 Collecting guided by ethnobotanical data has been applied in two ways to drug 

 discovery programs. One approach is the study of the uses o£-v arious plants in 

 traditional medicine, followed by a testing of their true effectiveness in these 

 applications. Positive results from this type of work depend upon careful disease 

 recognition and precise documentation of uses of herbal remedies. The second 

 approach has been random screening of plants used in traditional medicine based 

 on the assumption that they have a higher probability of yielding bioactive 

 compounds. The use of the ethnobotanical approach has the advantage of 

 providing a 'prescreen' for bioactive compounds (Miller & Brewer, 1992). 



Monsanto-^Sparlp's Plant Scn-ftPninP Pmtrratn 



The challenge to the technologists using the random screening technique is to 

 obtain a large and diverse collection of chemicals. The natural diversity found in 

 plants is almost infinitely large because it is the product of the interplay of both 

 genetic environmental factors. Therefore, over the past four years, Monsanto- 

 Searle has collaborated with the Missouri Botanical Gardens in St Louis to obtain 

 approximately 10,000 plant samples for use in both drug and agrochemicEil 

 discovery programs using the random collection strategy. These samples have 



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