Guy T Carter

Morphine rNCH3

Morphine

OH OH

Quinine

Quinine

Penicillin G

HOOCH

OH OH

Penicillin G

Vancomycin r"H

Vancomycin

O CH3

Artemisinin r"H

O CH3

Artemisinin

Chlortetracycline (a tetracycline antibiotic)

y"

xdhy "*CONH

Chlortetracycline (a tetracycline antibiotic)

y"

Erythromycin A (a macrolide antibiotic)

FIGURE 6.1 Examples from the major classes of natural products.

originally described as basic compounds found predominantly in plants. Alkaloids have varied biosynthetic origins, frequently based on an amino acid core; the unifying structural aspect remains the existence of a basic nitrogen function. Examples of well-known alkaloids that have been used in medicine are morphine (from the opium poppy, Papaver somniferum) and quinine (from Chincona species).

Closely related to alkaloids are the peptides, that are composed largely of amino acids, often with unusual structural modifications. These peptides are characteristically much smaller than proteins, generally less than 2000 Da in molecular weight, and are usually not assembled on the ribosome. As shown in Figure 6.1, the powerful antibiotics, penicillin and vancomycin, are representatives of nonribosomally synthesized peptide natural products that have great utility in modern medicine.

Terpenoids comprise a highly diverse class of secondary metabolites, whose members are constituted by combinations of five-carbon units. These segments are commonly referred to as "isoprenoid units" that are biogenetically derived from one of two alternative pathways, either through mevalonic acid or deoxyxylulose phosphate. Traditionally, these compounds have been characterized as monoterpenes (C10), e.g., menthol and camphor; sesiquiterpenes (C15), e.g., artemisinin; diterpenes (C20), e.g., paclitaxel (Taxol®); and so on to sesterterpenes (C25), and triterpenes (C30). The obvious structural diversity is derived from cation-induced rearrangements of the nascent isoprenyl chain to form a large variety of cyclic frameworks.

Polyketides are the result of an exceptionally versatile biosynthetic pathway that assembles polyfunctional compounds by sequential condensation of small carboxylic acid units, followed by various steps, such as reductive processing, "tailoring" reactions, and cyclization. The range of structural diversity of polyketides is so vast that it is difficult to summarize with only a few examples, so for illustration two of the best known antibiotic polyketides, tetracycline and erythromycin are shown in Figure 6.1.

These biosynthetic origins remain basically the same across the phylogenetic spectrum; however, the distribution of various pathways is highly dependent on the type of organism. Polyketides and nonribosomally synthesized peptides, particularly those with antimicrobial activity have been primarily isolated from bacteria and fungi. Higher plants are historically the most prolific sources of terpenes and alkaloids. Since higher plants are readily accessible they were the first sources to be explored for medicinal properties.

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