Preface

The story of natural products is, in many ways, the story of chemistry itself. It begins with investigations into natural products created by the organisms that inhabit the world around us and continues in ever increasing levels of detail as techniques for investigation grow in sophistication. In that sense, with a focus on ever more intricate details, the study of natural products conforms to the reductionist principles of chemistry. This is then followed by the attempts of chemists to mimic (or improve upon) nature by synthesising natural products and analogues with improved qualities. The first part of this book considers the isolation, structure elucidation and synthesis of natural products using previously published material as examples. The book then considers the complexity of living systems and the collision between approaches to natural products driven by reductionist chemistry and those driven by the living systems within which natural products are produced and upon which they have impacts. Once again, published material is used as an anchor point for each chapter. Chemistry is, however, more than just the application of techniques to solve problems and the nature of empiricism (where properties are measured directly) and extrapolation from a given knowledge base to deduce details from imperfect information is also considered along with the philosophical basis for the study of natural products.

While the study of chemicals in isolation is perhaps the best way of measuring their properties in absolute terms, molecules in general and natural products in particular do not generally exist in isolation. Reductionism and even empiricism can only produce a certain amount of imperfect knowledge of how a natural product operates within a living system. The challenge is that a whole living system is incredibly complex and developing tools to measure effects will have to focus on specific aspects of a living system and not the whole organism. As we interrogate specific aspects of a living system which is being perturbed by the intervention of a natural product, the following questions arise: can a whole system be considered to be simply the sum of its parts or is there more to living systems? If we can split a mixture of natural products according to biological activity, can we treat living systems in a similar manner? Is there truth in the idea of vitalism? The synthesis of a natural product from first principles (i.e., from molecules that are not initially derived from living systems) would seem to suggest that, on a molecular level, vitalism is not a coherent philosophy. If the same principles apply to living systems, then it should be possible to reduce a complex living system to a number of partial models which can, at the very least, provide a comparison of the impact of different natural products on a living system. A number of such model systems are considered.

While it is tempting to consider that living systems are a collection of interrelated biological reactions, the situation is much more complex. This creates the question of why biosynthetic reactions proceed to the final product and the concept of ‘molecular free will’. What are the properties of natural products which mean that they are formed in the first place? Is a sequence of enzyme reactions that make up a biosynthetic pathway an irreversible process and what does this tell us about natural products and their relationship to living systems. Do individual reactions in a biosynthetic sequence have sufficient biological autonomy to be studied in isolation in a meaningful way?

Living systems are both complex and efficient. In addition, the role of biological systems may not correspond with the initial view of the chemist and their reductionist principles. In the case of plant cell walls, the phenolic structures created by the plant could arise from enzymatic or non-enzymatic processes. In each case, the formation of specific (and very complex) products is controlled by the molecular orientation of the precursor molecules. This in turn dictates the physicochemical properties of the cell wall and may have other functions that relate to the nature of the environment in which plants grow and are not necessarily obvious to the observing chemist.

Living systems are not simply passive acceptors of bioactive natural products and the nature of bioactivation and subsequent biological reactions are considered using a specific group of molecules (pyrrolizidine alkaloids) as examples. As noted, living systems are not passive recipients of natural products and this may suggest that living systems are more than the sum of their parts. This concept is examined and eventually discarded.

Many biological systems have a rapid and measurable reaction to biologically active natural products; however, much of the exposure of living systems to natural products is often of a chronic rather than an acute form. Examples illustrating these two extremes are allergens – which provoke an immediate and escalating reaction and metabolic toxins whose effect is much less extreme and the endpoint must be deduced by extrapolation. In each case, appropriate model systems must be derived but for different reasons. Testing allergens by administration to sensitive individuals could result in anaphylaxis or even death, while lifetime exposure experiments are costly, prone to significant confounders and of limited use because of inter-individual variation. The use of human cells in culture can be of value in these cases.

The definition of natural products is an important defining characteristic and this, together with the activity of the same natural products at different sites in the body, is considered. The clash between molecular reductionism, as practiced by the natural product chemist, and the multiplicity of biological responses provides an important inflexion point in the chemical–biological interaction landscape.

The final chapter provides a brief review of some of the salient points considered in the other chapters and also summarises the philosophical questions and challenges raised. The book begins with a view from the standpoint of natural product chemistry and builds a structure of the interaction of natural products with living systems. Both reductionism and complexity are a part of the study of natural products. The former gives just a partial picture while the latter is difficult, if not impossible, to interpret.

Bryan Hanley