For survival purposes, all living organisms rely on an ability to transform and interconvert a diverse set of organic and inorganic compounds in order to utilize them as a source of energy and as their structural building blocks. The presence of these crucial building molecules, the “primary metabolites” (amino acids, fatty acids, nucleosides, and sugars) can be considered synonymous with “life” since they are ubiquitous among all organisms. While the role of primary metabolism for the survival of species can be appreciated readily, the rationale for the presence of some other compounds with no apparent role in the internal economy of the producing organism is not so clearly evident. These small-molecule organic compounds of considerable structural diversity and typically a limited taxonomical distribution, the “secondary metabolites,” are believed to provide the producing organisms with a survival advantage. Support for this may be inferred from the observation that organisms lacking immune systems (e.g. higher and lower plants, algae, fungi and microorganisms) generally show a high abundance of these compounds.38 The term “natural product” is usually used interchangeably with “secondary metabolite” for the purposes of drug discovery from organisms. It is found commonly that plants, like other organisms, tend to produce a series of analogues of a given structural type, rather than only one main secondary metabolite of a given class. It has been argued that over millions of years, the compounds providing a survival advantage are preserved (and even fine-tuned structurally through biosynthetic modification), while the not-so-active analogues are eliminated through evolutionary pressure.
Plants interact chemically with other organisms such as insects, microorganisms, other plants, and even mammals as a result of their secondary metabolites, leading to a multitude of biological responses. Clearly, since secondary metabolites are produced at the expense of the producing organism, it would be expected that this “chemical artillery” must offer the plant some advantage against its potential adversaries. Secondary metabolites mostly exert their effects by acting through enzyme or protein interactions. While some of these compounds act as substrates at the receptor level and mimic the endogenous substances in the target organism, others simply disrupt protein-protein interactions necessary for normal cell function.Therefore, it might be concluded that it is this ability of secondary metabolites to interact with the physiology of other species that renders them as an impressive source of “evolutionarily fine-tuned” drug-like molecules.
Drug discovery efforts from plants has been evolving continuously in response to a number of recent technological advances, such as the development of chromatographic methods that allow reproducible and fast purification steps for diverse compound classes; the availability of sensitive spectroscopic methods permitting the structural characterization of samples in microgram quantities; efficient chemical methods that permit the synthesis, derivatization, and optimization of bioactive lead compounds; and the wide accessibility of diverse sets of bioassays that provide the natural products chemist with critical information to target bioactive compounds from the early stages of separation studies.
The standard practice in plant natural products isolation chemistry for drug discovery can be broken down into five steps, namely, organism collection, extraction, compound isolation, structure determination, and bioassay. Plant samples are authenticated taxonomically and extracted with a solvent of choice and the resultant extracts are screened against pharmacologically relevant targets. Once a positive result is achieved, isolation studies follow, guided by the relevant bioassay studies using the so-called “activity-guided fractionation” technique. When an active principle is isolated, thorough spectroscopic and spectrometric or Xray crystallographic methods are employed as needed for the unambiguous assignment of its structure and configuration. In the pharmaceutical industry and in other laboratories with considerable resources, many of the above-mentioned techniques are employed along with combinatorial and synthetic chemistry efforts, as well as computational modeling and chemical informatics studies coupled with specific high-throughput screening methods.