Plant cell culture combined with chemistry: a powerful route to complex natural products

The combination of plant cell culture methodology with synthetic chemistry affords an attractive route to the synthesis of complex natural products and related compounds of industrial importance. Plant cell cultures which often provide "unique" enzyme systems can be employed effectively as "reagents" in the biotransformation of synthetic substrates to desired end products. Such conversions are often superior to those utilizing chemical reagents with the result that the overall synthetic route is more efficient. Alternatively, the use of plant cell culture derived enzymes in the evaluation of biosynthetic pathways can often afford important information for synthetic design. The overall strategy illustrating such an approach is presented herein with specific examples. Introduction The plant kingdom has provided a wide variety of natural products with diverse chemical structures and a vast array of biological activities, many of which have found applications in the health sciences. For years, synthetic chemists have been afforded the challenge of developing syntheses of such components but often due to structural complexity the resulting multi-step syntheses rarely find application in large scale production as required in the pharmaceutical drug industry. As a result, starting materials for such drug production, or indeed the final clinical drug, are frequently obtained from tedious and often costly extraction from the living plant. This latter solution is often fraught with the well known problems: a) active agent present in minute amounts in the plant extract; b) separation of target compound may be difficult and, in turn, expensive; c) varying concentrations of the target compound depending on seasons during which plant collection is performed; d) desired plant species growing in geographically or politically inaccessible regions, etc. Appropriate solutions to at least some of the above difficulties are possible by the use of plant cell culture methodology particularly when such studies are coupled with chemical methods. The advantages of plant cell cultures over living plants, in terms of secondary metabolite production, are clear: a) growth conditions are laboratory controlled, therefore, reproducible yields of end product are achieved; b) growth parameters such as pH, changes in nutrient media, temperature, etc. can be optimized to achieve metabolite production in yields significantly higher than in the living plant; c) separation of target compounds is much easier due to lower complexity of extract; d) cloning of cell lines provides further optimization for end product yields; e) plant cell cultures are an excellent source of enzymes, much superior to living plants where isolation often leads to enzyme denaturation. With enzyme availability, the opportunity to perform biosynthetic and/or biotransformation experiments related to metabolite production, is clear. It must be emphasized at the outset that the effectiveness of such a program depends entirely on an interdisciplinary "team" of scientists comprised of the "culture development" group (biologists, biochemists) and the "chemical" group, the latter isolating and characterizing the metabolites via spectroscopic methods coupled with synthesis as required.