Lead compounds secondary metabolites

Secondary metabolites with similar structural types and pharmacophoric groups can be seen in several bacteria (where they are often termed antibiotics if they have antimicrobial or cytotoxic properties). Since eukaryotic cells had taken up a-proteobacteria (which became mitochondria) and cyanobacteria (which became chloroplasts), they also inherited a number of genes that encode enzymes for pathways leading to secondary metabolites. Therefore, we may speculate that early plants already had the capacity of building defense compounds and that alkaloids were among the first. Since the numbers and types of herbivores and other enemies have increased within the last 100 million years, angiosperms have had to face more enemies and as a consequence have developed a more complex pattern of defense and signal compounds. 

Sesquiterpenes, as already reported in the previous sections, are the most widespread Lactarius metabolites however, a few species possess a particular metabolism which leads to secondary metabolites of other classes. Moreover, interesting new compounds with a different biogenesis have been isolated also from species producing large quantities of sesquiterpenes. 

Growth and diet are subject to seasonal changes. The presence (or absence) and relative concentrations of secondary metabolites in the extracts of organisms are factors which chemists should document along with observations made during collection. Often, in preliminary experiments guided by bioassay, mixtures, rather than individual compounds, are tested. Association of a certain activity with structurally related compounds may serve as a lead for further tests, but should not be considered definitive. 

Most of the antibiotics commercially available nowadays are derivatives of natural compounds produced by bacteria or fungi. It is widely accepted that in nature these secondary metabolites can act as weapons for microbial cell defence, inhibiting the growth of competitors. However, it seems that antibiotics have, in nature, more sophisticated and complex functions [1-3]. Many environmental bacteria can not only cope with natural antimicrobial substances but also benefit from their presence. For instance, the use of antibiotics by bacteria as biochemical signals, modulators of metabolic activity or even carbon sources has been demonstrated [1, 2, 4]. In other cases, antibiotics can be tolerated because they have structures similar to the natural substrates of bacterial housekeeping enzymes and thus are inactivated, leading to a natural form of resistance [2]. These are just some... 

The discovery of novel, small molecules through screening secondary microbial metabolites is still an important and fruitful activity in pharmaceutical and biotech industries. However, the isolation and structure elucidation of lead compounds is often a tedious and time-consuming process especially when the compounds being sought may only be present in infinitesimal quantities. When one considers, for example, that microorganism extracts have thousands of constituents, the difficulties in separating out one particular component can be appreciated. 

The marine environment clearly holds a tremendous potential for the discovery of lead compounds for development of agents active against infectious diseases and parasites. Within the vast resource of marine flora and fauna are new chemotypes to stem the tide of drug-resistant microbes and insects. Tapping this biological reserve depends on the technology to collect, rapidly recognize, and characterize trace quantities of secondary metabolites. Recent advances in life-support systems and analytical instrumentation, notably with CCUBA, HPLC, NMR, and MS have made this possible. 

Metabolites from cyanobacteria are generally of amino acid or polyketide origin and frequently show potent biological activity. The series of dolastatin metabolites, exemplified by dolastatin-10 (Structure 2.18), are linear peptides which show potent cytotoxic activity and are of clinical interest as anti-tumour agents. Originally isolated in very low yield from the Indian Ocean sea hare Dolabella auricularia, dolastatins are now known to be cyanobacterial products.43,44 The discovery of a microbial source for these pharmaceutically important compounds will facilitate study of their biosynthesis and could potentially lead to the production of structural analogues by provision of modified biosynthetic precursors to the cultivar. As discussed below and in Section VI, toxic secondary metabolites from cyanobacteria have often been implicated in the chemical defenses of sea hares.45"17... 

In addition to the primary metabolic reactions, which are similar in all living organisms, a vast number of metabolic pathways lead to the formation of compounds peculiar to a few species or even to a single chemical race only. These reactions are summed up under the term secondary metabolism, and their products are called secondary metabolites (Grierson, 1993 Herbert, 1989 Porter and Spurgeon, 1981, 1983 Stafford, 1990). 

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